chr21-46121586-C-A

Position:

chr21-46121586-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001849.4(COL6A2):c.1489C>A(p.Pro497Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.64

Variant links:

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

COL6A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014317423).

BP6

Variant 21-46121586-C-A is Benign according to our data. Variant chr21-46121586-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284555.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A2	NM_001849.4 linkuse as main transcript	c.1489C>A	p.Pro497Thr	missense_variant	18/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3 linkuse as main transcript	c.1489C>A	p.Pro497Thr	missense_variant	18/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3 linkuse as main transcript	c.1489C>A	p.Pro497Thr	missense_variant	18/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.1489C>A	p.Pro497Thr	missense_variant	18/28	1	NM_001849.4	ENSP00000300527	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.1489C>A	p.Pro497Thr	missense_variant	18/28	5	NM_058174.3	ENSP00000380870		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.1489C>A	p.Pro497Thr	missense_variant	17/27	5		ENSP00000387115		P12110-3
COL6A2	ENST00000413758.1 linkuse as main transcript	c.112C>A	p.Pro38Thr	missense_variant	3/11	3		ENSP00000395751

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00658

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000416

AC:

104

AN:

249838

Hom.:

AF XY:

0.000413

AC XY:

AN XY:

135578

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00539

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000139

AC:

203

AN:

1460530

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00463

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000236

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00660

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000454

Hom.:

Bravo

AF:

0.000204

ExAC

AF:

0.000355

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2018

A variant of uncertain significance has been identified in the COL6A2 gene. The P497T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P497T variant is observed in 41/8600 (0.5%) alleles from individuals of East Asian background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P497T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 24, 2015

- -

Myosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

- -

COL6A2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;.;.;.;D

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

T;T;.;T;T

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.014

T;T;T;T;T

MetaSVM

Uncertain

0.61

MutationAssessor

Uncertain

2.5

M;M;M;M;.

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.3

D;D;D;D;D

REVEL

Uncertain

0.59

Sift

Benign

0.053

T;D;D;D;D

Sift4G

Benign

0.097

T;T;T;T;D

Polyphen

0.87

P;P;P;P;.

Vest4

0.53

MVP

0.99

MPC

0.20

ClinPred

0.10

GERP RS

4.2

Varity_R

0.18

gMVP

0.34

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