rs112010940

chr2-237381341-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004369.4(COL6A3):c.1471G>C(p.Asp491His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00589 in 1,614,220 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D491V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (63 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.13

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004274994).
• BP6: Variant 2-237381341-C-G is Benign according to our data. Variant chr2-237381341-C-G is described in ClinVar as [Benign]. Clinvar id is 94907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237381341-C-G is described in Lovd as [Benign]. Variant chr2-237381341-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00529 (806/152344) while in subpopulation SAS AF= 0.0133 (64/4826). AF 95% confidence interval is 0.0107. There are 4 homozygotes in gnomad4. There are 426 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.1471G>C	p.Asp491His	missense_variant	5/44	ENST00000295550.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.1471G>C	p.Asp491His	missense_variant	5/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 806 AN: 152226 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00579

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00744 AC: 1871 AN: 251462 Hom.: 23 AF XY: 0.00814 AC XY: 1106 AN XY: 135906

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.0369

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0117

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00668

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.00595 AC: 8696 AN: 1461876 Hom.: 63 Cov.: 32 AF XY: 0.00630 AC XY: 4578 AN XY: 727242

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.0342

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.0100

Gnomad4 NFE exome AF: 0.00504

Gnomad4 OTH exome AF: 0.00709

GnomAD4 genome AF: 0.00529 AC: 806 AN: 152344 Hom.: 4 Cov.: 33 AF XY: 0.00572 AC XY: 426 AN XY: 74494

Gnomad4 AFR AF: 0.000817

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.0429

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.00579

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00899 Hom.: 8

Bravo AF: 0.00377

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00746 AC: 906

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00752

EpiControl AF: 0.00765

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 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	Feb 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COL6A3: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.84	T;T;T;T;.;D;D;D
MetaRNN	Benign	0.0043	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.3	N;N;D;.;N;D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0040	D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Polyphen		0.50	P;B;.;.;P;.;.;.
Vest4		0.41
MVP		0.78
MPC		0.45
ClinPred		0.025	T
GERP RS		4.4
Varity_R		0.36
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112010940; hg19: chr2-238289984;