rs150432347

Positions:

chr21-46003568-C-T

Variant summary

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

The NM_001848.3(COL6A1):c.2642C>T(p.Thr881Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,612,642 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0015 ( 6 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.495

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:

COL6A1 (HGNC:):

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=0.007489562).

BP6

Variant 21-46003568-C-T is Benign according to our data. Variant chr21-46003568-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93863.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3 linkuse as main transcript	c.2642C>T	p.Thr881Met	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 linkuse as main transcript	c.2642C>T	p.Thr881Met	missense_variant	35/35	1	NM_001848.3	ENSP00000355180.3		P12109

Frequencies

GnomAD3 genomes

AF:

0.000847

AC:

129

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000696

AC:

171

AN:

245540

Hom.:

AF XY:

0.000694

AC XY:

AN XY:

134054

show subpopulations

Gnomad AFR exome

AF:

0.000450

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.0000560

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.00137

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.00154

AC:

2250

AN:

1460304

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

1087

AN XY:

726510

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.000134

Gnomad4 NFE exome

AF:

0.00191

Gnomad4 OTH exome

AF:

0.00142

GnomAD4 genome

AF:

0.000847

AC:

129

AN:

152338

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00163

Hom.:

Bravo

AF:

0.000929

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000710

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2024	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	This variant is associated with the following publications: (PMID: 30564623, 15689448) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.10

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0075

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.69

N;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.67

N;.

REVEL

Benign

0.18

Sift

Benign

0.084

T;.

Sift4G

Benign

0.068

T;T

Polyphen

0.81

P;.

Vest4

0.12

MVP

0.39

MPC

0.67

ClinPred

0.018

GERP RS

-4.9

Varity_R

0.016

gMVP

0.33

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