rs2270671

Positions:

• chr2-237334642-G-A

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.9213C>T​(p.His3071=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,242 control chromosomes in the GnomAD database, including 8,824 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (794 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8030 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.14

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=-0.67).
• BP6: Variant 2-237334642-G-A is Benign according to our data. Variant chr2-237334642-G-A is described in ClinVar as [Benign]. Clinvar id is 95019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237334642-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.9213C>T	p.His3071=	synonymous_variant	41/44	ENST00000295550.9
COL6A3	NM_057167.4	c.8595C>T	p.His2865=	synonymous_variant	40/43
COL6A3	NM_057166.5	c.7392C>T	p.His2464=	synonymous_variant	38/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.9213C>T	p.His3071=	synonymous_variant	41/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15396 AN: 152104 Hom.: 794 Cov.: 32

Gnomad AFR AF: 0.0940

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0429

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.107 AC: 26915 AN: 251126 Hom.: 1517 AF XY: 0.109 AC XY: 14731 AN XY: 135748

Gnomad AFR exome AF: 0.0934

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.0393

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.103 AC: 150771 AN: 1461020 Hom.: 8030 Cov.: 31 AF XY: 0.104 AC XY: 75623 AN XY: 726816

Gnomad4 AFR exome AF: 0.0953

Gnomad4 AMR exome AF: 0.124

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.0472

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.101 AC: 15402 AN: 152222 Hom.: 794 Cov.: 32 AF XY: 0.102 AC XY: 7627 AN XY: 74410

Gnomad4 AFR AF: 0.0939

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.0428

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.112

Alfa AF: 0.103 Hom.: 435

Bravo AF: 0.101

Asia WGS AF: 0.0790 AC: 277 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.107

ClinVar

Significance: Benign

Submissions summary: Benign:10

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, 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	GeneDx	Feb 11, 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	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 24. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2012	- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.58
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2270671; hg19: chr2-238243285;