rs10084221

Positions:

• chr2-237344689-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004369.4(COL6A3):​c.7329C>T​(p.Ala2443Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,609,996 control chromosomes in the GnomAD database, including 1,654 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (687 hom., cov: 32)
  • Exomes 𝑓: 0.023 (967 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.192

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-237344689-G-A is Benign according to our data. Variant chr2-237344689-G-A is described in ClinVar as [Benign]. Clinvar id is 94985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237344689-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.192 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.7329C>T	p.Ala2443Ala	synonymous_variant	36/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.6711C>T	p.Ala2237Ala	synonymous_variant	35/43		NP_476508.2
COL6A3	NM_057166.5	c.5508C>T	p.Ala1836Ala	synonymous_variant	33/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.7329C>T	p.Ala2443Ala	synonymous_variant	36/44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes AF: 0.0636 AC: 9673 AN: 151992 Hom.: 687 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.00425

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0603

GnomAD3 exomes AF: 0.0320 AC: 7974 AN: 249010 Hom.: 354 AF XY: 0.0296 AC XY: 3988 AN XY: 134906

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0427

Gnomad EAS exome AF: 0.00408

Gnomad SAS exome AF: 0.0265

Gnomad FIN exome AF: 0.00763

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0230 AC: 33544 AN: 1457886 Hom.: 967 Cov.: 34 AF XY: 0.0227 AC XY: 16441 AN XY: 724732

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.0258

Gnomad4 ASJ exome AF: 0.0431

Gnomad4 EAS exome AF: 0.00182

Gnomad4 SAS exome AF: 0.0260

Gnomad4 FIN exome AF: 0.00929

Gnomad4 NFE exome AF: 0.0180

Gnomad4 OTH exome AF: 0.0327

GnomAD4 genome AF: 0.0637 AC: 9683 AN: 152110 Hom.: 687 Cov.: 32 AF XY: 0.0612 AC XY: 4548 AN XY: 74354

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.0364

Gnomad4 ASJ AF: 0.0412

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.0237

Gnomad4 FIN AF: 0.00754

Gnomad4 NFE AF: 0.0196

Gnomad4 OTH AF: 0.0597

Alfa AF: 0.0442 Hom.: 156

Bravo AF: 0.0717

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.0239

EpiControl AF: 0.0253

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 20, 2017	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.0
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs10084221; hg19: chr2-238253332;