rs35993209

chr2-237347855-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004369.4(COL6A3):c.6981A>G(p.Glu2327=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,610,310 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (81 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (81 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.452

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-237347855-T-C is Benign according to our data. Variant chr2-237347855-T-C is described in ClinVar as [Benign]. Clinvar id is 94977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237347855-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.452 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.6981A>G	p.Glu2327=	synonymous_variant	31/44	ENST00000295550.9
COL6A3	NM_057167.4	c.6363A>G	p.Glu2121=	synonymous_variant	30/43
COL6A3	NM_057166.5	c.5160A>G	p.Glu1720=	synonymous_variant	28/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.6981A>G	p.Glu2327=	synonymous_variant	31/44	1	NM_004369.4	P1
COL6A3	ENST00000472056.5	c.5160A>G	p.Glu1720=	synonymous_variant	28/41	1
COL6A3	ENST00000353578.9	c.6363A>G	p.Glu2121=	synonymous_variant	30/43	5
COL6A3	ENST00000491769.1	n.1235A>G		non_coding_transcript_exon_variant	8/20	5

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2579 AN: 152176 Hom.: 77 Cov.: 32

Gnomad AFR AF: 0.0576

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00778

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00498 AC: 1217 AN: 244218 Hom.: 33 AF XY: 0.00384 AC XY: 506 AN XY: 131632

Gnomad AFR exome AF: 0.0588

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000446

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.000680

Gnomad OTH exome AF: 0.00546

GnomAD4 exome AF: 0.00220 AC: 3210 AN: 1458016 Hom.: 81 Cov.: 32 AF XY: 0.00196 AC XY: 1423 AN XY: 724674

Gnomad4 AFR exome AF: 0.0587

Gnomad4 AMR exome AF: 0.00614

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000435

Gnomad4 FIN exome AF: 0.000282

Gnomad4 NFE exome AF: 0.000475

Gnomad4 OTH exome AF: 0.00564

GnomAD4 genome AF: 0.0171 AC: 2597 AN: 152294 Hom.: 81 Cov.: 32 AF XY: 0.0162 AC XY: 1203 AN XY: 74474

Gnomad4 AFR AF: 0.0578

Gnomad4 AMR AF: 0.00777

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00797 Hom.: 15

Bravo AF: 0.0192

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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)	Jul 17, 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	Apr 01, 2016	- -
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. -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 20, 2017

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.6
Dann	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35993209; hg19: chr2-238256498;