rs140441798

chr2-237340723-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_004369.4(COL6A3):c.8193A>C(p.Pro2731=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,614,106 control chromosomes in the GnomAD database, including 3 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 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (3 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.91

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-237340723-T-G is Benign according to our data. Variant chr2-237340723-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288516.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.8193A>C	p.Pro2731=	synonymous_variant	38/44	ENST00000295550.9
COL6A3	NM_057167.4	c.7575A>C	p.Pro2525=	synonymous_variant	37/43
COL6A3	NM_057166.5	c.6372A>C	p.Pro2124=	synonymous_variant	35/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.8193A>C	p.Pro2731=	synonymous_variant	38/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000322 AC: 81 AN: 251210 Hom.: 0 AF XY: 0.000376 AC XY: 51 AN XY: 135768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000405

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000532 AC: 778 AN: 1461870 Hom.: 3 Cov.: 33 AF XY: 0.000549 AC XY: 399 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000562

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74438

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000412 Hom.: 0

Bravo AF: 0.000253

EpiCase AF: 0.000218

EpiControl AF: 0.000533

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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	COL6A3: BP4, BP7 -

COL6A3-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.85
Cadd	Benign	0.93
Dann	Benign	0.38

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: rs140441798; hg19: chr2-238249366;