rs13051496

Positions:

chr21-46003595-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 Benign.

Frequency

Genomes: 𝑓 0.15 ( 2235 hom., cov: 36)

Exomes 𝑓: 0.20 ( 31910 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.21

Variant links:

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]

COL6A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
COL6A1	NM_001848.3 link	c.2669C>T	p.Ser890Leu	missense_variant	35/35	ENST00000361866.8	NP_001839.2	P12109A0A384P5H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 link	c.2669C>T	p.Ser890Leu	missense_variant	35/35	1	NM_001848.3	ENSP00000355180.3		P12109

Frequencies

GnomAD3 genomes

AF:

0.154

AC:

23404

AN:

152172

Hom.:

2235

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.200

AC XY:

145438

AN XY:

726590

show subpopulations

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.:

AF XY:

0.152

AC XY:

11288

AN XY:

74460

show subpopulations

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 04, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;.

PrimateAI

Uncertain

0.65

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over