rs376564984

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001849.4(COL6A2):c.503G>T(p.Ser168Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000634 in 1,608,146 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.27

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A2	NM_001849.4 linkuse as main transcript	c.503G>T	p.Ser168Ile	missense_variant	3/28	ENST00000300527.9
COL6A2	NM_058174.3 linkuse as main transcript	c.503G>T	p.Ser168Ile	missense_variant	3/28	ENST00000397763.6
COL6A2	NM_058175.3 linkuse as main transcript	c.503G>T	p.Ser168Ile	missense_variant	3/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.503G>T	p.Ser168Ile	missense_variant	3/28	1	NM_001849.4	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.503G>T	p.Ser168Ile	missense_variant	3/28	5	NM_058174.3		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.503G>T	p.Ser168Ile	missense_variant	2/27	5			P12110-3
COL6A2	ENST00000436769.5 linkuse as main transcript	c.503G>T	p.Ser168Ile	missense_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152174

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000426

AC:

AN:

234476

Hom.:

AF XY:

0.00

AC XY:

AN XY:

129528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000960

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000659

AC:

AN:

1455972

Hom.:

Cov.:

AF XY:

0.0000649

AC XY:

AN XY:

724084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000838

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000852

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Center for Genetic Medicine Research, Children's National Medical Center

Dec 01, 2015

- -

Bethlem myopathy 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 168 of the COL6A2 protein (p.Ser168Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Ullrich congenital muscular dystrophy (PMID: 27854218). ClinVar contains an entry for this variant (Variation ID: 224688). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL6A2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

Cadd

Uncertain

Dann

Benign

0.93

DEOGEN2

Uncertain

0.50

D;.;T;.;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;D;.;D

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.44

T;T;T;T;T

MetaSVM

Uncertain

0.020

MutationAssessor

Benign

1.8

L;L;.;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

N;N;D;N;N

REVEL

Uncertain

0.50

Sift

Uncertain

0.0080

D;D;D;D;D

Sift4G

Uncertain

0.022

D;D;D;D;D

Polyphen

0.88

P;P;.;P;P

Vest4

0.47

MVP

0.91

MPC

0.46

ClinPred

0.75

GERP RS

3.4

Varity_R

0.39

gMVP

0.80

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