rs146355600

chr2-237365917-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6 BP7 BS1

The NM_004369.4(COL6A3):c.5619C>T(p.His1873=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000602 in 1,614,176 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (1 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.50

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-237365917-G-A is Benign according to our data. Variant chr2-237365917-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166942.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000606 (886/1461828) while in subpopulation MID AF= 0.0085 (49/5768). AF 95% confidence interval is 0.0066. There are 1 homozygotes in gnomad4_exome. There are 471 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.5619C>T	p.His1873=	synonymous_variant	12/44	ENST00000295550.9
COL6A3	NM_057167.4	c.5001C>T	p.His1667=	synonymous_variant	11/43
COL6A3	NM_057166.5	c.3798C>T	p.His1266=	synonymous_variant	9/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.5619C>T	p.His1873=	synonymous_variant	12/44	1	NM_004369.4	P1
COL6A3	ENST00000472056.5	c.3798C>T	p.His1266=	synonymous_variant	9/41	1
COL6A3	ENST00000353578.9	c.5001C>T	p.His1667=	synonymous_variant	11/43	5

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000597 AC: 150 AN: 251246 Hom.: 0 AF XY: 0.000640 AC XY: 87 AN XY: 135842

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000775

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000606 AC: 886 AN: 1461828 Hom.: 1 Cov.: 32 AF XY: 0.000648 AC XY: 471 AN XY: 727208

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000571

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.000564 AC: 86 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74492

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000616

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2020	This variant is associated with the following publications: (PMID: 18825676) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	COL6A3: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine 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
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.43
Dann	Benign	0.40

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: rs146355600; hg19: chr2-238274560;