rs11690358

Positions:

• chr2-237336138-T-C

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.8962A>G​(p.Met2988Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0953 in 1,613,478 control chromosomes in the GnomAD database, including 8,196 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (491 hom., cov: 33)
  • Exomes 𝑓: 0.098 (7705 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.05

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=0.0013721287).
• BP6: Variant 2-237336138-T-C is Benign according to our data. Variant chr2-237336138-T-C is described in ClinVar as [Benign]. Clinvar id is 95013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237336138-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.8962A>G	p.Met2988Val	missense_variant	40/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.8344A>G	p.Met2782Val	missense_variant	39/43		NP_476508.2
COL6A3	NM_057166.5	c.7141A>G	p.Met2381Val	missense_variant	37/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.8962A>G	p.Met2988Val	missense_variant	40/44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes AF: 0.0723 AC: 10999 AN: 152178 Hom.: 490 Cov.: 33

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0498

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.0637

Gnomad FIN AF: 0.0911

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0692

GnomAD3 exomes AF: 0.0758 AC: 18824 AN: 248494 Hom.: 881 AF XY: 0.0780 AC XY: 10523 AN XY: 134956

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.0402

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0100

Gnomad SAS exome AF: 0.0638

Gnomad FIN exome AF: 0.0943

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0752

GnomAD4 exome AF: 0.0977 AC: 142820 AN: 1461182 Hom.: 7705 Cov.: 31 AF XY: 0.0967 AC XY: 70320 AN XY: 726876

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.0424

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.00967

Gnomad4 SAS exome AF: 0.0651

Gnomad4 FIN exome AF: 0.0932

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.0904

GnomAD4 genome AF: 0.0722 AC: 11001 AN: 152296 Hom.: 491 Cov.: 33 AF XY: 0.0705 AC XY: 5253 AN XY: 74466

Gnomad4 AFR AF: 0.0313

Gnomad4 AMR AF: 0.0497

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.00946

Gnomad4 SAS AF: 0.0635

Gnomad4 FIN AF: 0.0911

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.0681

Alfa AF: 0.0936 Hom.: 1222

Bravo AF: 0.0686

TwinsUK AF: 0.116 AC: 431

ALSPAC AF: 0.108 AC: 418

ESP6500AA AF: 0.0244 AC: 100

ESP6500EA AF: 0.0908 AC: 749

ExAC AF: 0.0753 AC: 9074

Asia WGS AF: 0.0480 AC: 166 AN: 3478

EpiCase AF: 0.101

EpiControl AF: 0.100

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2017	- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.039
DANN	Benign	0.54
DEOGEN2	Benign	0.13	.;T;.;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.12	T;T;T;T;.
MetaRNN	Benign	0.0014	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-1.0	.;N;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.0	N;N;N;.;N
REVEL	Benign	0.18
Sift	Benign	1.0	T;T;T;.;T
Sift4G	Benign	0.61	T;T;T;T;T
Polyphen		0.0	B;B;.;.;B
Vest4		0.013
MPC		0.15
ClinPred		0.000010	T
GERP RS		-4.8
Varity_R		0.057
gMVP		0.078

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs11690358; hg19: chr2-238244781; COSMIC: COSV55108394; COSMIC: COSV55108394;