rs139498556

chr2-237381274-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_004369.4(COL6A3):c.1538G>A(p.Arg513Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R513W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: -0.00900

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06901318).
• BP6: Variant 2-237381274-C-T is Benign according to our data. Variant chr2-237381274-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288877.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.1538G>A	p.Arg513Gln	missense_variant	5/44	ENST00000295550.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.1538G>A	p.Arg513Gln	missense_variant	5/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000390 AC: 98 AN: 251456 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135900

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000571

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000250 AC: 366 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.000220 AC XY: 160 AN XY: 727242

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000276

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74376

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000322 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000527 AC: 64

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2023	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30564623) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 23, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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. -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Pathogenic	1.0
Eigen	Benign	0.058
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.069	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N;N;N;.;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.20	T;T;T;.;T;T;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;.;.;D;.;.;.
Vest4		0.54
MVP		0.73
MPC		0.68
ClinPred		0.83	D
GERP RS		5.5
Varity_R		0.20
gMVP		0.42

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: rs139498556; hg19: chr2-238289917; COSMIC: COSV55114015;