rs79606264

chr2-237388126-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004369.4(COL6A3):c.768C>T(p.Val256=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,614,168 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 33)
  • Exomes 𝑓: 0.015 (245 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.09

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=-0.68).
• BP6: Variant 2-237388126-G-A is Benign according to our data. Variant chr2-237388126-G-A is described in ClinVar as [Benign]. Clinvar id is 94995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237388126-G-A is described in Lovd as [Benign]. Variant chr2-237388126-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.012 (1827/152342) while in subpopulation SAS AF= 0.0292 (141/4824). AF 95% confidence interval is 0.0253. There are 18 homozygotes in gnomad4. There are 893 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.768C>T	p.Val256=	synonymous_variant	4/44	ENST00000295550.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.768C>T	p.Val256=	synonymous_variant	4/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1826 AN: 152224 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00697

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0147 AC: 3648 AN: 248904 Hom.: 48 AF XY: 0.0162 AC XY: 2187 AN XY: 134746

Gnomad AFR exome AF: 0.00629

Gnomad AMR exome AF: 0.00729

Gnomad ASJ exome AF: 0.0267

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0351

Gnomad FIN exome AF: 0.00942

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0148 AC: 21581 AN: 1461826 Hom.: 245 Cov.: 32 AF XY: 0.0156 AC XY: 11318 AN XY: 727214

Gnomad4 AFR exome AF: 0.00729

Gnomad4 AMR exome AF: 0.00800

Gnomad4 ASJ exome AF: 0.0272

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0336

Gnomad4 FIN exome AF: 0.00912

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0120 AC: 1827 AN: 152342 Hom.: 18 Cov.: 33 AF XY: 0.0120 AC XY: 893 AN XY: 74500

Gnomad4 AFR AF: 0.00697

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0154 Hom.: 16

Bravo AF: 0.0114

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0173

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 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	Feb 18, 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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	9.4
Dann	Benign	0.71

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: rs79606264; hg19: chr2-238296769;