21-46125455-AC-ACC

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The NM_001849.4(COL6A2):c.1817-3dupC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,609,932 control chromosomes in the GnomAD database, including 16,150 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1289 hom., cov: 30)

Exomes 𝑓: 0.13 ( 14861 hom. )

Consequence

COL6A2
NM_001849.4 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.481

Publications

4 publications found

Variant links:

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

COL6A2 Gene-Disease associations (from GenCC):

collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Ullrich congenital muscular dystrophy 1B
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
Bethlem myopathy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
Ullrich congenital muscular dystrophy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myosclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

COL6A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.5, offset of 0 (no position change), new splice context is: gaccctgccaccccccccAGact. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 21-46125455-A-AC is Benign according to our data. Variant chr21-46125455-A-AC is described in ClinVar as Benign. ClinVar VariationId is 93925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
COL6A2	NM_001849.4	MANE Select	c.1817-3dupC	splice_acceptor intron	N/A	NP_001840.3
COL6A2	NM_058174.3	MANE Plus Clinical	c.1817-3dupC	splice_acceptor intron	N/A	NP_478054.2
COL6A2	NM_058175.3		c.1817-3dupC	splice_acceptor intron	N/A	NP_478055.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.1817-3dupC		splice_acceptor intron	N/A	ENSP00000300527.4
COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1817-3dupC		splice_acceptor intron	N/A	ENSP00000380870.1
COL6A2	ENST00000413758.1	TSL:3	c.485dupC	p.Asp163ArgfsTer3	frameshift	Exon 10 of 11	ENSP00000395751.1

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18039

AN:

151672

Hom.:

1289

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0921

Gnomad AMI

AF:

0.0782

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.120

Gnomad EAS

AF:

0.348

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.0589

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.128

Gnomad OTH

AF:

0.140

GnomAD2 exomes

AF:

0.130

AC:

32417

AN:

249506

AF XY:

0.128

show subpopulations

Gnomad AFR exome

AF:

0.0940

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.117

Gnomad EAS exome

AF:

0.338

Gnomad FIN exome

AF:

0.0609

Gnomad NFE exome

AF:

0.128

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

AF:

0.133

AC:

193389

AN:

1458142

Hom.:

14861

Cov.:

AF XY:

0.131

AC XY:

95357

AN XY:

725414

show subpopulations

African (AFR)

AF:

0.0905

AC:

3025

AN:

33436

American (AMR)

AF:

0.120

AC:

5375

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

3124

AN:

26106

East Asian (EAS)

AF:

0.408

AC:

16189

AN:

39636

South Asian (SAS)

AF:

0.0930

AC:

8020

AN:

86216

European-Finnish (FIN)

AF:

0.0639

AC:

3335

AN:

52176

Middle Eastern (MID)

AF:

0.112

AC:

642

AN:

5756

European-Non Finnish (NFE)

AF:

0.131

AC:

145595

AN:

1109826

Other (OTH)

AF:

0.134

AC:

8084

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

8684

17368

26051

34735

43419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5326

10652

15978

21304

26630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.119

AC:

18046

AN:

151790

Hom.:

1289

Cov.:

AF XY:

0.118

AC XY:

8765

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.0920

AC:

3806

AN:

41388

American (AMR)

AF:

0.121

AC:

1851

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

417

AN:

3468

East Asian (EAS)

AF:

0.348

AC:

1782

AN:

5116

South Asian (SAS)

AF:

0.104

AC:

497

AN:

4794

European-Finnish (FIN)

AF:

0.0589

AC:

622

AN:

10562

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.128

AC:

8675

AN:

67908

Other (OTH)

AF:

0.141

AC:

298

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

804

1608

2413

3217

4021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

392

588

784

980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0655

Hom.:

110

Bravo

AF:

0.124

EpiCase

AF:

0.133

EpiControl

AF:

0.132

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 19, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: High allele frequency.

Bethlem myopathy 1A

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Myosclerosis

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Collagen 6-related myopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

May 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.48

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over