2-237339091-C-G

Position:

• chr2-237339091-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.8491G>C​(p.Asp2831His) variant causes a missense change. The variant allele was found at a frequency of 0.0831 in 1,612,822 control chromosomes in the GnomAD database, including 6,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (369 hom., cov: 33)
  • Exomes 𝑓: 0.086 (5931 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.46

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

COL6A3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027243495).
• BP6: Variant 2-237339091-C-G is Benign according to our data. Variant chr2-237339091-C-G is described in ClinVar as [Benign]. Clinvar id is 95006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237339091-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.088 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.8491G>C	p.Asp2831His	missense_variant	39/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.7873G>C	p.Asp2625His	missense_variant	38/43		NP_476508.2
COL6A3	NM_057166.5	c.6670G>C	p.Asp2224His	missense_variant	36/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.8491G>C	p.Asp2831His	missense_variant	39/44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8959 AN: 152024 Hom.: 367 Cov.: 33

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0700

Gnomad FIN AF: 0.0583

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0899

Gnomad OTH AF: 0.0523

GnomAD3 exomes AF: 0.0655 AC: 16463 AN: 251286 Hom.: 691 AF XY: 0.0689 AC XY: 9356 AN XY: 135826

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.0322

Gnomad ASJ exome AF: 0.0971

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0729

Gnomad FIN exome AF: 0.0594

Gnomad NFE exome AF: 0.0894

Gnomad OTH exome AF: 0.0737

GnomAD4 exome AF: 0.0856 AC: 125027 AN: 1460680 Hom.: 5931 Cov.: 30 AF XY: 0.0857 AC XY: 62301 AN XY: 726710

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.0339

Gnomad4 ASJ exome AF: 0.0912

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0754

Gnomad4 FIN exome AF: 0.0622

Gnomad4 NFE exome AF: 0.0944

Gnomad4 OTH exome AF: 0.0898

GnomAD4 genome AF: 0.0589 AC: 8961 AN: 152142 Hom.: 369 Cov.: 33 AF XY: 0.0551 AC XY: 4095 AN XY: 74358

Gnomad4 AFR AF: 0.0172

Gnomad4 AMR AF: 0.0453

Gnomad4 ASJ AF: 0.0931

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0709

Gnomad4 FIN AF: 0.0583

Gnomad4 NFE AF: 0.0899

Gnomad4 OTH AF: 0.0508

Alfa AF: 0.0787 Hom.: 437

Bravo AF: 0.0575

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.0992 AC: 853

ExAC AF: 0.0671 AC: 8147

Asia WGS AF: 0.0290 AC: 103 AN: 3478

EpiCase AF: 0.0963

EpiControl AF: 0.0930

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 25, 2017	- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Benign	0.18	.;T;.;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;.
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.7	.;M;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D;D;N;.;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.30
MPC		0.18
ClinPred		0.038	T
GERP RS		5.1
Varity_R		0.31
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs36104025; hg19: chr2-238247734;