rs140534207

Positions:

chr21-46003561-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000361866.8(COL6A1):c.2635A>G(p.Ser879Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,612,558 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S879S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 35)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

COL6A1
ENST00000361866.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 3.19

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011149317).

BP6

Variant 21-46003561-A-G is Benign according to our data. Variant chr21-46003561-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162529.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=3, Uncertain_significance=2}. Variant chr21-46003561-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3 linkuse as main transcript	c.2635A>G	p.Ser879Gly	missense_variant	35/35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 linkuse as main transcript	c.2635A>G	p.Ser879Gly	missense_variant	35/35	1	NM_001848.3	ENSP00000355180	P1

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00800

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00173

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00182

AC:

446

AN:

245210

Hom.:

AF XY:

0.00181

AC XY:

243

AN XY:

133930

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.000378

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000852

Gnomad FIN exome

AF:

0.00887

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00183

GnomAD4 exome

AF:

0.00125

AC:

1820

AN:

1460246

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

912

AN XY:

726474

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.0000767

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000835

Gnomad4 FIN exome

AF:

0.00776

Gnomad4 NFE exome

AF:

0.00112

Gnomad4 OTH exome

AF:

0.000961

GnomAD4 genome

AF:

0.00144

AC:

219

AN:

152312

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00800

Gnomad4 NFE

AF:

0.00174

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.000661

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00187

AC:

227

EpiCase

AF:

0.00136

EpiControl

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	COL6A1: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 15, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2016	The S879G variant in the COL6A1 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. This variant is a non-conservative amino acid substitution of a polar Serine with a non-polar Glycine at a residue that is conserved across species. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. The S879G variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. We interpret S879G as a variant of unknown significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2015

- -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.55

DEOGEN2

Benign

0.35

T;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.72

T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.091

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.5

N;.

REVEL

Uncertain

0.53

Sift

Benign

0.47

T;.

Sift4G

Benign

0.39

T;T

Polyphen

1.0

D;.

Vest4

0.28

MVP

0.63

MPC

0.68

ClinPred

0.074

GERP RS

4.8

Varity_R

0.20

gMVP

0.81

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