rs13051496

chr21-46003595-C-T

Variant summary

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

The NM_001848.3(COL6A1):c.2669C>T(p.Ser890Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,612,760 control chromosomes in the GnomAD database, including 34,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S890S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2235 hom., cov: 36)
  • Exomes 𝑓: 0.20 (31910 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.21

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022459328).
• BP6: Variant 21-46003595-C-T is Benign according to our data. Variant chr21-46003595-C-T is described in ClinVar as [Benign]. Clinvar id is 93865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46003595-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.2669C>T	p.Ser890Leu	missense_variant	35/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.2669C>T	p.Ser890Leu	missense_variant	35/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23404 AN: 152172 Hom.: 2235 Cov.: 36

Gnomad AFR AF: 0.0581

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0720

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.142

GnomAD3 exomes AF: 0.161 AC: 39804 AN: 246710 Hom.: 3874 AF XY: 0.166 AC XY: 22334 AN XY: 134436

Gnomad AFR exome AF: 0.0547

Gnomad AMR exome AF: 0.0858

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.0699

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.202 AC: 295295 AN: 1460470 Hom.: 31910 Cov.: 80 AF XY: 0.200 AC XY: 145438 AN XY: 726590

Gnomad4 AFR exome AF: 0.0564

Gnomad4 AMR exome AF: 0.0901

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.0646

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.218

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.187

GnomAD4 genome AF: 0.154 AC: 23403 AN: 152290 Hom.: 2235 Cov.: 36 AF XY: 0.152 AC XY: 11288 AN XY: 74460

Gnomad4 AFR AF: 0.0581

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.0718

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.214

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.141

Alfa AF: 0.190 Hom.: 1960

Bravo AF: 0.143

TwinsUK AF: 0.225 AC: 835

ALSPAC AF: 0.216 AC: 834

ESP6500AA AF: 0.0558 AC: 246

ESP6500EA AF: 0.216 AC: 1859

ExAC AF: 0.161 AC: 19511

Asia WGS AF: 0.0740 AC: 259 AN: 3478

EpiCase AF: 0.214

EpiControl AF: 0.213

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 31, 2017

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.19
Sift	Uncertain	0.019	D;.
Sift4G	Benign	0.063	T;T
Polyphen		0.13	B;.
Vest4		0.10
MPC		0.34
ClinPred		0.017	T
GERP RS		4.0
Varity_R		0.18
gMVP		0.43

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: rs13051496; hg19: chr21-47423509; COSMIC: COSV62611834; COSMIC: COSV62611834;