rs111803773

Positions:

• chr2-237344618-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004369.4(COL6A3):​c.7400C>T​(p.Ser2467Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,614,152 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S2467S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (3 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.48

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006082624).
• BP6: Variant 2-237344618-G-A is Benign according to our data. Variant chr2-237344618-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94986.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr2-237344618-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00207 (315/152276) while in subpopulation AFR AF= 0.00707 (294/41562). AF 95% confidence interval is 0.00641. There are 2 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.7400C>T	p.Ser2467Leu	missense_variant	36/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.6782C>T	p.Ser2261Leu	missense_variant	35/43		NP_476508.2
COL6A3	NM_057166.5	c.5579C>T	p.Ser1860Leu	missense_variant	33/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.7400C>T	p.Ser2467Leu	missense_variant	36/44	1	NM_004369.4	ENSP00000295550	P1

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152158 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00709

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000541 AC: 136 AN: 251384 Hom.: 0 AF XY: 0.000368 AC XY: 50 AN XY: 135864

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000213 AC: 311 AN: 1461876 Hom.: 3 Cov.: 34 AF XY: 0.000186 AC XY: 135 AN XY: 727234

Gnomad4 AFR exome AF: 0.00681

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152276 Hom.: 2 Cov.: 32 AF XY: 0.00193 AC XY: 144 AN XY: 74446

Gnomad4 AFR AF: 0.00707

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000342 Hom.: 0

Bravo AF: 0.00227

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000667 AC: 81

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2017	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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.7400C>T (p.S2467L) alteration is located in exon 36 (coding exon 35) of the COL6A3 gene. This alteration results from a C to T substitution at nucleotide position 7400, causing the serine (S) at amino acid position 2467 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

COL6A3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 20, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	.;D;.;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;D;.
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.0061	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	.;M;.;.;.
MutationTaster	Benign	0.63	D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D;D;D;.;D
REVEL	Benign	0.035
Sift	Benign	0.044	D;D;D;.;D
Sift4G	Uncertain	0.037	D;T;T;T;D
Polyphen		0.73	P;D;.;.;P
Vest4		0.41
MVP		0.69
MPC		0.13
ClinPred		0.023	T
GERP RS		5.1
Varity_R		0.15
gMVP		0.37

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: rs111803773; hg19: chr2-238253261;