rs11903206

Positions:

• chr2-237336278-G-A
• chr2-237336278-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004369.4(COL6A3):​c.8822C>T​(p.Ala2941Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,046 control chromosomes in the GnomAD database, including 96 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (54 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (42 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.978

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028971434).
• BP6: Variant 2-237336278-G-A is Benign according to our data. Variant chr2-237336278-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237336278-G-A is described in Lovd as [Pathogenic]. Variant chr2-237336278-G-A is described in Lovd as [Benign]. Variant chr2-237336278-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (2031/152354) while in subpopulation AFR AF= 0.0451 (1876/41570). AF 95% confidence interval is 0.0434. There are 54 homozygotes in gnomad4. There are 934 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 54 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.8822C>T	p.Ala2941Val	missense_variant	40/44	ENST00000295550.9
COL6A3	NM_057167.4	c.8204C>T	p.Ala2735Val	missense_variant	39/43
COL6A3	NM_057166.5	c.7001C>T	p.Ala2334Val	missense_variant	37/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.8822C>T	p.Ala2941Val	missense_variant	40/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2022 AN: 152236 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0450

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00386 AC: 968 AN: 250624 Hom.: 23 AF XY: 0.00304 AC XY: 413 AN XY: 135734

Gnomad AFR exome AF: 0.0465

Gnomad AMR exome AF: 0.00396

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000546

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00167 AC: 2438 AN: 1461692 Hom.: 42 Cov.: 32 AF XY: 0.00150 AC XY: 1092 AN XY: 727144

Gnomad4 AFR exome AF: 0.0460

Gnomad4 AMR exome AF: 0.00461

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000348

Gnomad4 OTH exome AF: 0.00406

GnomAD4 genome AF: 0.0133 AC: 2031 AN: 152354 Hom.: 54 Cov.: 33 AF XY: 0.0125 AC XY: 934 AN XY: 74500

Gnomad4 AFR AF: 0.0451

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00453 Hom.: 9

Bravo AF: 0.0152

ESP6500AA AF: 0.0418 AC: 184

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00469 AC: 569

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000830

ClinVar

Significance: Benign/Likely 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	Eurofins Ntd Llc (ga)	Jul 17, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 01, 2016	- -
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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COL6A3: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Collagen 6-related myopathy Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.79
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.65	T;T;T;T;.
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.58	N;N;N;.;N
REVEL	Benign	0.10
Sift	Benign	0.042	D;D;D;.;D
Sift4G	Benign	0.31	T;T;T;T;T
Polyphen		0.0070	B;B;.;.;B
Vest4		0.10
MVP		0.61
MPC		0.15
ClinPred		0.0039	T
GERP RS		-1.6
Varity_R		0.045
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11903206; hg19: chr2-238244921; COSMIC: COSV99040623; COSMIC: COSV99040623;