rs13879

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001848.3(COL6A1):c.2736C>T(p.Asp912=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,613,080 control chromosomes in the GnomAD database, including 690 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 49 hom., cov: 35)

Exomes 𝑓: 0.027 ( 641 hom. )

Consequence

COL6A1
NM_001848.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.37

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 21-46003662-C-T is Benign according to our data. Variant chr21-46003662-C-T is described in ClinVar as [Benign]. Clinvar id is 93866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46003662-C-T is described in Lovd as [Benign]. Variant chr21-46003662-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.37 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0201 (3060/152366) while in subpopulation NFE AF= 0.0305 (2076/68036). AF 95% confidence interval is 0.0294. There are 49 homozygotes in gnomad4. There are 1431 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 49 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3 linkuse as main transcript	c.2736C>T	p.Asp912=	synonymous_variant	35/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8 linkuse as main transcript	c.2736C>T	p.Asp912=	synonymous_variant	35/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0201

AC:

3061

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00600

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.0403

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00993

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0305

Gnomad OTH

AF:

0.0224

GnomAD3 exomes

AF:

0.0203

AC:

5046

AN:

248808

Hom.:

AF XY:

0.0206

AC XY:

2781

AN XY:

135144

show subpopulations

Gnomad AFR exome

AF:

0.00429

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.0364

Gnomad EAS exome

AF:

0.000221

Gnomad SAS exome

AF:

0.00762

Gnomad FIN exome

AF:

0.0125

Gnomad NFE exome

AF:

0.0316

Gnomad OTH exome

AF:

0.0218

GnomAD4 exome

AF:

0.0270

AC:

39453

AN:

1460714

Hom.:

641

Cov.:

AF XY:

0.0266

AC XY:

19361

AN XY:

726678

show subpopulations

Gnomad4 AFR exome

AF:

0.00376

Gnomad4 AMR exome

AF:

0.0140

Gnomad4 ASJ exome

AF:

0.0379

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00817

Gnomad4 FIN exome

AF:

0.0128

Gnomad4 NFE exome

AF:

0.0312

Gnomad4 OTH exome

AF:

0.0253

GnomAD4 genome

AF:

0.0201

AC:

3060

AN:

152366

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1431

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00599

Gnomad4 AMR

AF:

0.0200

Gnomad4 ASJ

AF:

0.0403

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00993

Gnomad4 FIN

AF:

0.0110

Gnomad4 NFE

AF:

0.0305

Gnomad4 OTH

AF:

0.0222

Alfa

AF:

0.0273

Hom.:

Bravo

AF:

0.0195

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0317

EpiControl

AF:

0.0357

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2012	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 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	PreventionGenetics, part of Exact Sciences	-	- -
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

Jan 31, 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. -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

Cadd

Benign

0.79

Dann

Benign

0.72

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