rs77181645

chr2-237378645-C-Achr2-237378645-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):c.2488G>T(p.Ala830Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 1,612,522 control chromosomes in the GnomAD database, including 533 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. A830T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (66 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (467 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0430

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=0.001642257).
• BP6: Variant 2-237378645-C-A is Benign according to our data. Variant chr2-237378645-C-A is described in ClinVar as [Benign]. Clinvar id is 94916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237378645-C-A is described in Lovd as [Benign]. Variant chr2-237378645-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.2488G>T	p.Ala830Ser	missense_variant	6/44	ENST00000295550.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.2488G>T	p.Ala830Ser	missense_variant	6/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1850 AN: 152162 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0592

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0456

Gnomad SAS AF: 0.0333

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0265 AC: 6653 AN: 251296 Hom.: 307 AF XY: 0.0237 AC XY: 3216 AN XY: 135864

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0432

Gnomad SAS exome AF: 0.0342

Gnomad FIN exome AF: 0.0288

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.00850 AC: 12416 AN: 1460242 Hom.: 467 Cov.: 33 AF XY: 0.00873 AC XY: 6342 AN XY: 726428

Gnomad4 AFR exome AF: 0.00171

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.0487

Gnomad4 SAS exome AF: 0.0318

Gnomad4 FIN exome AF: 0.0266

Gnomad4 NFE exome AF: 0.000780

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0121 AC: 1850 AN: 152280 Hom.: 66 Cov.: 33 AF XY: 0.0152 AC XY: 1131 AN XY: 74468

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.0594

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0451

Gnomad4 SAS AF: 0.0331

Gnomad4 FIN AF: 0.0339

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.0143

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0226 AC: 2748

Asia WGS AF: 0.0540 AC: 188 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000356

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	GeneDx	Mar 18, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 14, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2018	- -
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 31, 2024

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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	Benign	0.075
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	12
Dann	Benign	0.88
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.70	T;T;.;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D;D;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.081
Sift	Benign	0.28	T;T;T;T;T
Sift4G	Benign	0.073	T;T;T;T;T
Polyphen		0.86	P;B;P;.;.
Vest4		0.14
MPC		0.17
ClinPred		0.0030	T
GERP RS		0.19
Varity_R		0.054
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs77181645; hg19: chr2-238287288; COSMIC: COSV55094227;