rs11553518

Positions:

chr21-46003126-A-G

Variant summary

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

The NM_001848.3(COL6A1):c.2441A>G(p.Lys814Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0165 in 1,614,024 control chromosomes in the GnomAD database, including 1,375 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K814Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 115 hom., cov: 34)

Exomes 𝑓: 0.017 ( 1260 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.75

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=0.0024976134).

BP6

Variant 21-46003126-A-G is Benign according to our data. Variant chr21-46003126-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 93859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46003126-A-G is described in Lovd as [Benign]. Variant chr21-46003126-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3 linkuse as main transcript	c.2441A>G	p.Lys814Arg	missense_variant	34/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8 linkuse as main transcript	c.2441A>G	p.Lys814Arg	missense_variant	34/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2277

AN:

152162

Hom.:

115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00606

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.0977

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00604

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0287

AC:

7212

AN:

251294

Hom.:

380

AF XY:

0.0314

AC XY:

4270

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00542

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.0154

Gnomad EAS exome

AF:

0.140

Gnomad SAS exome

AF:

0.0980

Gnomad FIN exome

AF:

0.00333

Gnomad NFE exome

AF:

0.00646

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0167

AC:

24418

AN:

1461744

Hom.:

1260

Cov.:

AF XY:

0.0191

AC XY:

13864

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00583

Gnomad4 AMR exome

AF:

0.0140

Gnomad4 ASJ exome

AF:

0.0170

Gnomad4 EAS exome

AF:

0.179

Gnomad4 SAS exome

AF:

0.0978

Gnomad4 FIN exome

AF:

0.00347

Gnomad4 NFE exome

AF:

0.00545

Gnomad4 OTH exome

AF:

0.0200

GnomAD4 genome

AF:

0.0150

AC:

2277

AN:

152280

Hom.:

115

Cov.:

AF XY:

0.0174

AC XY:

1294

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00606

Gnomad4 AMR

AF:

0.0154

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.0982

Gnomad4 FIN

AF:

0.00282

Gnomad4 NFE

AF:

0.00603

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.0121

Hom.:

Bravo

AF:

0.0143

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.00709

AC:

ExAC

AF:

0.0304

AC:

3691

Asia WGS

AF:

0.0950

AC:

329

AN:

3478

EpiCase

AF:

0.00802

EpiControl

AF:

0.00794

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2013	- -
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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	-	- -

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. -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.28

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

0.000085

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.27

Sift

Benign

0.067

T;.

Sift4G

Uncertain

0.044

D;D

Polyphen

0.016

B;.

Vest4

0.30

MPC

0.21

ClinPred

0.015

GERP RS

3.4

Varity_R

0.089

gMVP

0.21

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