rs878854386

Positions:

chr21-46120540-G-A

Variant summary

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

The NM_001849.4(COL6A2):c.1358G>A(p.Arg453His) variant causes a missense change. The variant allele was found at a frequency of 0.000075 in 1,479,442 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R453C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.69

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.1358G>A	p.Arg453His	missense_variant	16/28	ENST00000300527.9
COL6A2	NM_058174.3 linkuse as main transcript	c.1358G>A	p.Arg453His	missense_variant	16/28	ENST00000397763.6
COL6A2	NM_058175.3 linkuse as main transcript	c.1358G>A	p.Arg453His	missense_variant	16/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.1358G>A	p.Arg453His	missense_variant	16/28	1	NM_001849.4	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.1358G>A	p.Arg453His	missense_variant	16/28	5	NM_058174.3		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.1358G>A	p.Arg453His	missense_variant	15/27	5			P12110-3
COL6A2	ENST00000413758.1 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000803

AC:

AN:

87126

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

45154

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000386

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000909

Gnomad OTH exome

AF:

0.000425

GnomAD4 exome

AF:

0.0000746

AC:

AN:

1327312

Hom.:

Cov.:

AF XY:

0.0000769

AC XY:

AN XY:

650282

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000117

Gnomad4 SAS exome

AF:

0.0000438

Gnomad4 FIN exome

AF:

0.0000439

Gnomad4 NFE exome

AF:

0.0000820

Gnomad4 OTH exome

AF:

0.0000734

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000219

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2015	The R453H variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was notobserved in approximately 5,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. The R453H variant is aconservative amino acid substitution, which is not likely to impact secondary protein structure as theseresidues share similar properties. However, this substitution occurs at a position that is conserved acrossspecies, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging tothe protein structure/function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 26, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	COL6A2: PP3 -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;T;.;D

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.66

D;D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

1.3

L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Pathogenic

0.71

Sift

Uncertain

0.025

D;D;D;D

Sift4G

Uncertain

0.045

D;T;T;T

Polyphen

1.0

D;D;D;D

Vest4

0.41

MutPred

0.48

Loss of methylation at R453 (P = 0.0062);Loss of methylation at R453 (P = 0.0062);Loss of methylation at R453 (P = 0.0062);Loss of methylation at R453 (P = 0.0062);

MVP

0.98

MPC

0.68

ClinPred

0.38

GERP RS

4.4

Varity_R

0.15

gMVP

0.48

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