Variant chr21-46125854-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The ENST00000300527.9(COL6A2):c.2039G>T(p.Arg680Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R680C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

COL6A2
ENST00000300527.9 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.95

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-46125853-CG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 422287.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A2	NM_001849.4 linkuse as main transcript	c.2039G>T	p.Arg680Leu	missense_variant	26/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3 linkuse as main transcript	c.2039G>T	p.Arg680Leu	missense_variant	26/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3 linkuse as main transcript	c.2039G>T	p.Arg680Leu	missense_variant	26/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.2039G>T	p.Arg680Leu	missense_variant	26/28	1	NM_001849.4	ENSP00000300527	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.2039G>T	p.Arg680Leu	missense_variant	26/28	5	NM_058174.3	ENSP00000380870		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.2039G>T	p.Arg680Leu	missense_variant	25/27	5		ENSP00000387115		P12110-3
COL6A2	ENST00000413758.1 linkuse as main transcript	c.710G>T	p.Arg237Leu	missense_variant	11/11	3		ENSP00000395751

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151870

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460778

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726704

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151870

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74134

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.;.;.;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D;.;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.75

D;D;D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.2

M;M;M;M;.

MutationTaster

Benign

0.000027

P;P;P;P;P

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.4

D;D;D;D;D

REVEL

Uncertain

0.52

Sift

Benign

0.036

D;D;D;D;T

Sift4G

Benign

0.14

T;T;T;T;D

Polyphen

1.0

D;P;P;D;.

Vest4

0.77

MutPred

0.41

Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);.;

MVP

0.68

MPC

0.68

ClinPred

0.99

GERP RS

4.4

Varity_R

0.54

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over