rs1042917

chr21-46125854-G-Achr21-46125854-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_001849.4(COL6A2):c.2039G>A(p.Arg680His) variant causes a missense change. The variant allele was found at a frequency of 0.483 in 1,612,622 control chromosomes in the GnomAD database, including 194,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R680?) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.45 (16357 hom., cov: 32)
  • Exomes 𝑓: 0.49 (177685 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.95

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=9.4074334E-5).
• BP6: Variant 21-46125854-G-A is Benign according to our data. Variant chr21-46125854-G-A is described in ClinVar as [Benign]. Clinvar id is 93929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46125854-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.2039G>A	p.Arg680His	missense_variant	26/28	ENST00000300527.9
COL6A2	NM_058174.3	c.2039G>A	p.Arg680His	missense_variant	26/28	ENST00000397763.6
COL6A2	NM_058175.3	c.2039G>A	p.Arg680His	missense_variant	26/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.2039G>A	p.Arg680His	missense_variant	26/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.2039G>A	p.Arg680His	missense_variant	26/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.2039G>A	p.Arg680His	missense_variant	25/27	5
COL6A2	ENST00000413758.1	c.710G>A	p.Arg237His	missense_variant	11/11	3

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67577 AN: 151798 Hom.: 16342 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.617

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.460

GnomAD3 exomes AF: 0.492 AC: 123178 AN: 250564 Hom.: 32074 AF XY: 0.482 AC XY: 65422 AN XY: 135706

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.653

Gnomad ASJ exome AF: 0.520

Gnomad EAS exome AF: 0.440

Gnomad SAS exome AF: 0.327

Gnomad FIN exome AF: 0.623

Gnomad NFE exome AF: 0.502

Gnomad OTH exome AF: 0.517

GnomAD4 exome AF: 0.487 AC: 711956 AN: 1460706 Hom.: 177685 Cov.: 72 AF XY: 0.483 AC XY: 350764 AN XY: 726668

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.644

Gnomad4 ASJ exome AF: 0.521

Gnomad4 EAS exome AF: 0.433

Gnomad4 SAS exome AF: 0.331

Gnomad4 FIN exome AF: 0.614

Gnomad4 NFE exome AF: 0.497

Gnomad4 OTH exome AF: 0.477

GnomAD4 genome AF: 0.445 AC: 67612 AN: 151916 Hom.: 16357 Cov.: 32 AF XY: 0.451 AC XY: 33455 AN XY: 74220

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.577

Gnomad4 ASJ AF: 0.524

Gnomad4 EAS AF: 0.450

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.617

Gnomad4 NFE AF: 0.509

Gnomad4 OTH AF: 0.455

Alfa AF: 0.481 Hom.: 36126

Bravo AF: 0.436

TwinsUK AF: 0.499 AC: 1851

ALSPAC AF: 0.516 AC: 1987

ESP6500AA AF: 0.241 AC: 1061

ESP6500EA AF: 0.501 AC: 4310

ExAC AF: 0.477 AC: 57872

Asia WGS AF: 0.402 AC: 1396 AN: 3478

EpiCase AF: 0.492

EpiControl AF: 0.489

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Bethlem myopathy 1A Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Myosclerosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30389748) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2017	- -

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. -

Ullrich congenital muscular dystrophy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T;T;.;T;T
MetaRNN	Benign	0.000094	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.5	L;L;L;L;.
MutationTaster	Benign	0.000071	P;P;P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.94	N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.081	T;T;T;D;T
Sift4G	Benign	0.13	T;T;T;T;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.43
MPC		0.68
ClinPred		0.011	T
GERP RS		4.4
Varity_R		0.22
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1042917; hg19: chr21-47545768; COSMIC: COSV56000676;