rs1042917

Variant names:

• chr21-46125854-G-A
• rs1042917
• NM_001849.4:c.2039G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46125854-G-A
• chr21-46125854-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001849.4(COL6A2):​c.2039G>A​(p.Arg680His) variant causes a missense change. The variant allele was found at a frequency of 0.483 in 1,612,622 control chromosomes in the GnomAD database, including 194,042 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R680C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.45 (16357 hom., cov: 32)
  • Exomes 𝑓: 0.49 (177685 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 4.95
• Publications: 54 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.4074334E-5).
• BP6: Variant 21-46125854-G-A is Benign according to our data. Variant chr21-46125854-G-A is described in ClinVar as [Benign]. Clinvar id is 93929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2039G>A	p.Arg680His	missense_variant	Exon 26 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2039G>A	p.Arg680His	missense_variant	Exon 26 of 28		NP_478054.2
COL6A2	NM_058175.3	c.2039G>A	p.Arg680His	missense_variant	Exon 26 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2039G>A	p.Arg680His	missense_variant	Exon 26 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.2039G>A	p.Arg680His	missense_variant	Exon 26 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.2039G>A	p.Arg680His	missense_variant	Exon 25 of 27	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.710G>A	p.Arg237His	missense_variant	Exon 11 of 11	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67577 AN: 151798 Hom.: 16342 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.617

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.460

GnomAD2 exomes AF: 0.492 AC: 123178 AN: 250564 AF XY: 0.482

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.653

Gnomad ASJ exome AF: 0.520

Gnomad EAS exome AF: 0.440

Gnomad FIN exome AF: 0.623

Gnomad NFE exome AF: 0.502

Gnomad OTH exome AF: 0.517

GnomAD4 exome AF: 0.487 AC: 711956 AN: 1460706 Hom.: 177685 Cov.: 72 AF XY: 0.483 AC XY: 350764 AN XY: 726668

African (AFR) AF: 0.229 AC: 7675 AN: 33480

American (AMR) AF: 0.644 AC: 28799 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13607 AN: 26132

East Asian (EAS) AF: 0.433 AC: 17172 AN: 39694

South Asian (SAS) AF: 0.331 AC: 28561 AN: 86256

European-Finnish (FIN) AF: 0.614 AC: 32193 AN: 52398

Middle Eastern (MID) AF: 0.431 AC: 2486 AN: 5768

European-Non Finnish (NFE) AF: 0.497 AC: 552640 AN: 1111894

Other (OTH) AF: 0.477 AC: 28823 AN: 60380

GnomAD4 genome AF: 0.445 AC: 67612 AN: 151916 Hom.: 16357 Cov.: 32 AF XY: 0.451 AC XY: 33455 AN XY: 74220

African (AFR) AF: 0.250 AC: 10381 AN: 41448

American (AMR) AF: 0.577 AC: 8807 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1818 AN: 3470

East Asian (EAS) AF: 0.450 AC: 2299 AN: 5110

South Asian (SAS) AF: 0.333 AC: 1601 AN: 4814

European-Finnish (FIN) AF: 0.617 AC: 6519 AN: 10564

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.509 AC: 34571 AN: 67928

Other (OTH) AF: 0.455 AC: 959 AN: 2106

Alfa AF: 0.477 Hom.: 78432

Bravo AF: 0.436

TwinsUK AF: 0.499 AC: 1851

ALSPAC AF: 0.516 AC: 1987

ESP6500AA AF: 0.241 AC: 1061

ESP6500EA AF: 0.501 AC: 4310

ExAC AF: 0.477 AC: 57872

Asia WGS AF: 0.402 AC: 1396 AN: 3478

EpiCase AF: 0.492

EpiControl AF: 0.489

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jul 31, 2012

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

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Bethlem myopathy 1A Benign:3

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

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Sep 13, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30389748) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Myosclerosis Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Ullrich congenital muscular dystrophy 1A Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T;T;.;T;T
MetaRNN	Benign	0.000094	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.5	L;L;L;L;.
PhyloP100		5.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.94	N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.081	T;T;T;D;T
Sift4G	Benign	0.13	T;T;T;T;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.43
MPC		0.68
ClinPred		0.011	T
GERP RS		4.4
Varity_R		0.22
gMVP		0.72
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1042917; hg19: chr21-47545768; COSMIC: COSV56000676;