Recommendations for the description of DNA sequence variants

Since references to WWW-sites are not yet acknowledged as citations, please mention den Dunnen JT and Antonarakis SE (2000). Hum.Mutat. 15: 7-12 when referring to these pages.

Contents

• Recommendations
  • general recommendations
    • nucleotide numbering
  • changes at DNA level
    • general
    • substitutions
    • deletions
    • duplications
      (incl. triplication, quadruplication, etc.)
    • insertions
    • variability of short sequence repeats
    • insertion/deletions  (indels)
    • inversions
    • conversions
    • translocations
    • two or more changes in one allele
    • uncertainties
    • complex
  • changes at RNA level
  • changes at protein level
• Explanations / examples
  • Quick Reference
  • changes at DNA level
  • changes at RNA level
  • changes at protein level

DNA level

(suggestions extending the published recommendations are in italics)

• nucleotides are designated by the bases (in upper case);
  • A (adenine)
  • C (cytosine)
  • G (guanine)
  • T (thymidine)
• nucleotide numbering  (for details and examples see Reference Sequence discussions)
  • coding DNA Reference Sequence  (see Examples and Figure)
    • there is no nucleotide 0
    • nucleotide 1 is the A of the ATG-translation initiation codon
    • the nucleotide 5' of the ATG-translation initiation codon is -1, the previous -2, etc.
    • the nucleotide 3' of the translation stop codon is *1, the next *2, etc.
    • intronic nucleotides for a coding DNA reference sequence
      • beginning of the intron; the number of the last nucleotide of the preceding exon, a plus sign and the position in the intron, like c.77+1G, c.77+2T, etc.
      • end of the intron; the number of the first nucleotide of the following exon, a minus sign and the position upstream in the intron, like c.78-1G.
      • in the middle of the intron, numbering changes from "c.77+.." to "c.78-.."; for introns with an uneven number of nucleotides the central nucleotide is the last described with a "+" (see Discussion)
      • NOTE: current opinions do not favour descriptions using the format c.IVS1+1G and c.IVS1-2G (see Discussion)
  • genomic Reference Sequence  (see Examples and Figure)
    • nucleotide numbering is purely arbitrary and starts with 1 at the first nucleotide of the database reference file
    • no +, - or other signs are used
    • the sequence should include all nucleotides covering the sequence (gene) of interest and should start well 5' of the promoter of a gene
    • when the complete genomic sequence is not known, a coding DNA reference sequence should be used
  • for all descriptions the most 3' position possible is arbitrarily assigned to have been changed (see Exception)

Substitutions

Single nucleotide substitutions are designated by a ">"-character (indicating "changes to"). Changes of two or more consecutive nucleotides are described as deletion/insertions (indels, see Deletion/insetions).

• c.76A>C denotes that at nucleotide 76 an A is changed to a C
• c.-14G>C denotes a G to C substitution 14 nucleotides 5' of the ATG translation initiation codon
• c.88+1G>T denotes the G to T substitution at nucleotide +1 of an intron (in the coding DNA positioned between nucleotides 88 and 89)
• c.89-2A>C denotes the A to C substitution at nucleotide -2 of an intron (in the coding DNA positioned between nucleotides 88 and 89)
• c.*46T>A denotes a T to A substitution 46 nucleotides 3' of the translation termination codon
• the description c.76_77delinsTT is preferred over c.[76A>T; 77G>T].

NOTE: it is not correct to describe polymorphic variants as c.76A/G (see Discussion). 

Deletions

Deletions are designated by "del" after an indication of the first and last nucleotide(s) deleted.

• c.76_78del (alternatively c.76_78delACT) denotes a ACT deletion from nucleotides 76 to 78
• c.7_8del (alternatively c.7_8delTG) denotes a TG deletion in the sequence ACTTTGTGCC to ACTTTGCC
• c.88-?_923+?del denotes an exonic deletion starting at an unknown position in the intron 5' of coding DNA nucleotide 88 and ending at an unknown position in the intron 3' of coding DNA nucleotide 923 (see Uncertainties)
• c.(?_-30)_(*220_?)del denotes the deletion of the entire gene (coding DNA reference sequence running from -30 (cap site) to *220 (polyA-addition site) (see Uncertainties)
• c.88+101_oGJB2:c.355-1045del denotes a deletion which ends in the flanking GJB2 gene at position 355-1045 (in the intron between nucleotides 354 and 355) on the reverse strand (the genes are thus located and fused in opposite transcriptional directions, see Discussion)
• for all descriptions the most 3' position possible is arbitrarily assigned to have been changed (see FAQ);
  • ACTTTGTGCC to ACTTGCC is described as c.5_7delTGT (not as c.4_6delTTG).
  • ctttagGCATG to cttagGTCCA in an intron is described as c.301-3delT (not as c.301-5delT)
  • TCACTGTCTGCGGTAATC to TCACTG CGGTAATC is described as c.7_10del (alternatively c.7_10delTCTG) and not as c.4_7delCTGT
  • AAAGAAGAGGAG to AAAG GAG is described as c.5_9del (alternatively c.5_9delAAGAG) and not as c.3_7delAGAAG
  • Exception
    • c.1210-12T(5_9) and not c.1210-6T(5_9)describes the variable stretch of 5 to 9 T-residues in intron 9 of the CFTR gene. The most commonly used CFTR coding DNA Reference Sequence contains a stretch of 7 T's (see Variability of short sequence repeats). 
      NOTE: to discriminate known variable sequences from other changes it is recommended to describe individual alleles differing from the reference sequence like c.1210-12T[5] (preferred over c.1210-7_1210-6delTT) or c.1210-12T[9] (preferred over c.1210-7_1210-6dupTT).
    • using a coding DNA Reference Sequence there is an exception to this rule when identical nucleotides flank an intron (e.g. exon 3 ends with ..CAAgt, exon 4 starts with agAAG.., C being nucleotide c.123). When the genomic sequence shows that the last A-nucleotide of exon 3 is deleted (and not the A-nucleotide in exon 4), the deletion changing ..CAAAAG.. to ..CA AAG.. is described as c.125delA and not c.127delA.

Duplications, triplications, ...

Duplications are designated by "dup" after an indication of the first and last nucleotide(s) duplicated.

• c.77_79dup (or c.77_79dupCTG, c.77_79dup3) denotes that the three nucleotides 77 to 79 are duplicated
• duplicating insertions of a mono-nucleotide and of extensions of di-, tri-, etc. nucleotide stretches should be described as duplications (see Discussion)
  • c.5dupT (or c.5dup) denotes a duplication ("insertion") of the T nucleotide at position 5 in the coding DNA sequence ACTCTGTGCC to ACTCTTGTGCC
  • c.5dupT (or c.5dup) denotes a duplication ("insertion") of the T nucleotide at position 5 in the coding DNA sequence ACTTTGTGCC to ACTTTTGTGCC
  • c.7_8dup (or c.7_8dupTG) or c.7_8dup2) denotes a TG duplication in the TG-tandem repeat sequence of ACTTTGTGCC to ACTTTGTGTGCC. NOTE: this change should not be described as an insertion, i.e. c.8_9insTG
• c.(?_-30)_(*220_?)dup denotes the duplication of the entire gene (coding DNA reference sequence running from -30 (cap site) to *220 (polyA-addition site) (see Uncertainties)
• c.32-?_357+?[3]  denotes a triplication of an exon (coding DNA reference sequence running from nucleotide 32 to 357, see Variability of short sequence repeats)
  NOTE: the use of tri (for triplication), qua (for quadruplication), etc. is not recommended (see Discussion)

Insertions

Insertions are designated by "ins" after an indication of the nucleotides flanking the insertion site, followed by a description of the nucleotides inserted. Duplicating insertions should be described as duplications (see Discussion), not as insertion. For large insertions the number of inserted nucleotides should be mentioned, together with an accession.version number referring to a sequence database file containing the complete inserted sequence. 

• c.76_77insT denotes that a T is inserted between nucleotides 76 and 77 of the coding DNA reference sequence
• c.123+54_123+55insAB012345.2:g.76_420 (or c.123+54_123+55ins345, GenBank AB012345.2) denotes an intronic insertion ( between nucleotides c.123+54 and 123+55) of 345 nucleotides (nucleotides 76 to 420 like in GenBank file AB012345 version 2)

Variability of short sequence repeats

Variability of short sequence repeats (e.g. ATGCGATGTGTGCC) are described as c.123+74TG(3_6); c.123+74 indicates the start of the first nucelotide of the variable repeat (not the end like c.123+79TG) and TG indicates the sequence of the repeat unit.
NOTE: the underscore is used to indicate the range (3 to 6 times); when the repeat-sequence becomes too large its size is indicated, not its range.

• c.1210-12T(5_9) describes a famous variable stretch of 5 to 9 T-residues in intron 9 of the CFTR gene. The most commonly used CFTR coding DNA Reference Sequence contains a stretch of 7 T's. It is recommended to describe individual alleles differing from this reference sequence as c.1210-12T[5] (not c.1210-7_1210-6delTT) or c.1210-12T[9] (not c.1210-7_1210-6dupTT).
  NOTE: the repeat should not be described as c.1210-6T(5_9)
• c.123+74TG(3_6) (alternatively c.123+74_123+75(3_6)) indicates that a TG di-nucleotide repeat is present, starting at nucleotide 74 in the intron following cDNA nucelotide c.123, which is found repeated 3 to 6 times in the population
  • c.123+74TG[4]+[5] denotes that a person carries a TG di-nucleotide repeat of length 4 on one allele and of length 5 on the other allele
• based on the FMR1 coding DNA Reference Sequence (GenBank NM_002024.3), c.-158GGC(1000) describes the presence of an extended GGC-repeat of about 1000 units
  NOTE: "()" is used to indicate uncertainties (see Uncertainties)
  • c.-158GGC[79] describes the presence of an extended GGC-repeat of exactly 79 units
• c.32-?_357+?[3]  denotes a triplication of an exon ( coding DNA reference sequence running from nucleotide 32 to 357, see Variability of short sequence repeats)
  NOTE: the use of tri (for triplication), qua (for quadruplication), etc. is not recommended (see Discussion)
• g.1209_4523(12_45) denotes that a 3.3 kb repeat sequence of which the first copy is present in the genomic reference sequence from nucleotides 1209 to 4523 can be found repeated 12 to 45 times in the population
  • g.1209_4523[14]+[23] denotes that a person carries a 3.3 kb repeat 14 times on one allele and of 23 times on the other allele

Deletion / insertions (indels)

Deletion/insertions (indels) are described as a deletion followed by an insertion after an indication of the nucleotides flanking the site of the deletion/insertion (see Discussion). Changes of two or more consecutive nucleotides are described as deletion/insertions (indels).

• c.112_117delinsTG (alternatively c.112_117delAGGTCAinsTG) denotes the replacement of nucleotides 112 to 117 (AGGTCA) by TG
• c.114_115delinsA (alternative c.[114G>A; 115delT])

Inversions

Inversions are designated by "inv" after an indication of the first and last nucleotides affected by the inversion.

• c.203_506inv (or 203_506inv304) denotes that the 304 nucleotides from position 203 to 506 have been inverted

Conversions

Conversions are designated by "con" after an indication of the first and last nucleotides affected by the conversion, followed by a description of the origin of the new nucleotides (see Discussion).

• c.123_678conNM_004006.1:c.123_678 describes a gene conversion replacing nucleotides c.123 to c.4567 of the coding DNA sequence of the transcript of interest with nucleotides c.123 to c.678 from a transcript sequence as present in GenBank file NM_004006 (version 1)

Translocations

Translocations are described at the molecular level using the format "t(X;4)(p21.2;q34)", followed by the usual numbering, indicating the position translocation breakpoint. The sequences of the translocation breakpoints need to be submitted to a sequence database (Genbank, EMBL, DDJB) and the accession.version numbers should be given (see Discussion).

• t(X;4)(p21.2;q35)(c.857+101_857+102) denotes a translocation breakpoint in the intron between coding DNA nucleotides 857+101 and 857+102, joining chromosome bands Xp21.2 and 4q34

More changes in one individual

Two or more changes in one individual are described by combining the changes, per allele (chromosome) between square brackets ("[]").

• c.[76A>C]+[76A>C] denotes a homozygous A to C change at nucleotide 76
• c.[76A>C]+[?] denotes a A to C change at nucleotide 76 in one allele and an unknown change in the other allele
• c.[76A>C]+[=] denotes a A to C change at nucleotide 76 in one allele and a normal sequence in the other allele (see FAQ)
• descriptions of sequence changes in different genes (e.g. for recessive diseases) are listed between square brackets, separated by a "+"-character and include a reference to the sequence (gene) changed; [DMD:c.76A>C]+[GJB:c.87delG] (see Discussion)

• c.[76A>C; 83G>C] denotes two changes in one allele; A to C change at nucleotide 76 and a G to C change at nucleotide 83

• c.[=, 83G>C] describes a mosaic case where at position 83 besides the normal sequence (a G, described as '=') also chromosomes are found containing a C (c.83G>C).

• c.[76A>C(+)283G>C] denotes that two changes were identified in one individual (an A to C change at nucleotide 76 and a G to C change at nucleotide 283), but it is not known whether these changes are in the same allele or in different alleles

Complex changes

Sequence changes can be very complex, involving several changes at a specific location. The description of such changes using the recommendations given above can become rather complicated and at some point, although literally correct, effectively meaningless. In such cases the recommendation is to submit the sequence that has been determined to GenBank and to use the accession.version number in the description.

• c.123_678conNM_004006.1:c.123_678 describes a gene conversion replacing nucleotides c.123 to c.4567 of the coding DNA sequence of the transcript of interest with nucleotides c.123 to c.678 from a transcript sequence as present in GenBank file NM_004006 (version 1)
• c.88+101_oGJB2:c.355-1045del denotes a deletion which ends in the flanking GJB2 gene at position 355-1045 (in the intron between nucleotides 354 and 355) on the reverse strand (the genes are thus located and fused in opposite transcriptional directions, see Discussion)
• c.123+54_123+55insAB012345.2:g.76_420 denotes an intronic insertion (between nucleotides c.123+54 and 123+55) of 345 nucleotides (nucleotides 76 to 420 like in GenBank file AB012345 version 2)

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