rs9981981

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001849.4(COL6A2):c.1770+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0521 in 1,612,788 control chromosomes in the GnomAD database, including 5,672 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 612 hom., cov: 32)

Exomes 𝑓: 0.051 ( 5060 hom. )

Consequence

COL6A2
NM_001849.4 splice_region, intron

Scores

Splicing: ADA: 0.0001405

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.935

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 21-46124924-G-A is Benign according to our data. Variant chr21-46124924-G-A is described in ClinVar as Benign. ClinVar VariationId is 93921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4 link	c.1770+4G>A	splice_region_variant, intron_variant	Intron 23 of 27	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 link	c.1770+4G>A	splice_region_variant, intron_variant	Intron 23 of 27		NP_478054.2	P12110-2
COL6A2	NM_058175.3 link	c.1770+4G>A	splice_region_variant, intron_variant	Intron 23 of 27		NP_478055.2	P12110-3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL6A2	ENST00000300527.9 link	c.1770+4G>A	splice_region_variant, intron_variant	Intron 23 of 27	1	NM_001849.4	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6 link	c.1770+4G>A	splice_region_variant, intron_variant	Intron 23 of 27	5		ENSP00000380870.1	P12110-2
COL6A2	ENST00000409416.6 link	c.1770+4G>A	splice_region_variant, intron_variant	Intron 22 of 26	5		ENSP00000387115.1	P12110-3
COL6A2	ENST00000413758.1 link	c.393+4G>A	splice_region_variant, intron_variant	Intron 8 of 10	3		ENSP00000395751.1	H7C0M5

Frequencies

GnomAD3 genomes

AF:

0.0661

AC:

10052

AN:

152172

Hom.:

611

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0856

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0755

Gnomad ASJ

AF:

0.0401

Gnomad EAS

AF:

0.347

Gnomad SAS

AF:

0.0920

Gnomad FIN

AF:

0.0250

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0360

Gnomad OTH

AF:

0.0821

GnomAD2 exomes

AF:

0.0751

AC:

18797

AN:

250168

AF XY:

0.0722

show subpopulations

Gnomad AFR exome

AF:

0.0901

Gnomad AMR exome

AF:

0.0895

Gnomad ASJ exome

AF:

0.0349

Gnomad EAS exome

AF:

0.339

Gnomad FIN exome

AF:

0.0257

Gnomad NFE exome

AF:

0.0378

Gnomad OTH exome

AF:

0.0578

GnomAD4 exome

AF:

0.0506

AC:

73919

AN:

1460498

Hom.:

5060

Cov.:

AF XY:

0.0514

AC XY:

37325

AN XY:

726546

show subpopulations

African (AFR)

AF:

0.0856

AC:

2867

AN:

33478

American (AMR)

AF:

0.0894

AC:

3999

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0369

AC:

965

AN:

26134

East Asian (EAS)

AF:

0.409

AC:

16227

AN:

39696

South Asian (SAS)

AF:

0.0790

AC:

6814

AN:

86252

European-Finnish (FIN)

AF:

0.0252

AC:

1315

AN:

52156

Middle Eastern (MID)

AF:

0.0728

AC:

420

AN:

5768

European-Non Finnish (NFE)

AF:

0.0339

AC:

37740

AN:

1111928

Other (OTH)

AF:

0.0592

AC:

3572

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

3845

7691

11536

15382

19227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1600

3200

4800

6400

8000

<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:

0.0660

AC:

10053

AN:

152290

Hom.:

612

Cov.:

AF XY:

0.0679

AC XY:

5056

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0853

AC:

3548

AN:

41572

American (AMR)

AF:

0.0754

AC:

1153

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0401

AC:

139

AN:

3470

East Asian (EAS)

AF:

0.347

AC:

1789

AN:

5158

South Asian (SAS)

AF:

0.0921

AC:

444

AN:

4822

European-Finnish (FIN)

AF:

0.0250

AC:

266

AN:

10622

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0360

AC:

2450

AN:

68024

Other (OTH)

AF:

0.0836

AC:

177

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

463

925

1388

1850

2313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0464

Hom.:

470

Bravo

AF:

0.0730

Asia WGS

AF:

0.169

AC:

588

AN:

3478

EpiCase

AF:

0.0411

EpiControl

AF:

0.0390

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

May 07, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2016

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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 06, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bethlem myopathy 1A

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

0.94

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.084

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over