rs141703710

Positions:

chr21-46112179-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001849.4(COL6A2):c.316G>A(p.Glu106Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,612,984 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 9 hom., cov: 32)

Exomes 𝑓: 0.012 ( 119 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.48

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009793192).

BP6

Variant 21-46112179-G-A is Benign according to our data. Variant chr21-46112179-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46112179-G-A is described in Lovd as [Pathogenic]. Variant chr21-46112179-G-A is described in Lovd as [Benign]. Variant chr21-46112179-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A2	NM_001849.4 linkuse as main transcript	c.316G>A	p.Glu106Lys	missense_variant	3/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3 linkuse as main transcript	c.316G>A	p.Glu106Lys	missense_variant	3/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3 linkuse as main transcript	c.316G>A	p.Glu106Lys	missense_variant	3/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.316G>A	p.Glu106Lys	missense_variant	3/28	1	NM_001849.4	ENSP00000300527	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.316G>A	p.Glu106Lys	missense_variant	3/28	5	NM_058174.3	ENSP00000380870		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.316G>A	p.Glu106Lys	missense_variant	2/27	5		ENSP00000387115		P12110-3
COL6A2	ENST00000436769.5 linkuse as main transcript	c.316G>A	p.Glu106Lys	missense_variant	3/3	2		ENSP00000390418

Frequencies

GnomAD3 genomes

AF:

0.00686

AC:

1044

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00665

AC:

1666

AN:

250404

Hom.:

AF XY:

0.00688

AC XY:

934

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.00204

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00592

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.00621

GnomAD4 exome

AF:

0.0118

AC:

17177

AN:

1460672

Hom.:

119

Cov.:

AF XY:

0.0114

AC XY:

8261

AN XY:

726630

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00496

Gnomad4 NFE exome

AF:

0.0146

Gnomad4 OTH exome

AF:

0.00821

GnomAD4 genome

AF:

0.00685

AC:

1044

AN:

152312

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

463

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00243

Gnomad4 AMR

AF:

0.00405

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00386

Gnomad4 NFE

AF:

0.0121

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.00697

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.00706

AC:

857

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0117

EpiControl

AF:

0.0115

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 06, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	COL6A2: BS1, BS2 -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2013	- -

Bethlem myopathy 1A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Collagen 6-related myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Ullrich congenital muscular dystrophy 1A;C1850671:Myosclerosis;CN029274:Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;T;.;.

Eigen

Benign

-0.018

Eigen_PC

Benign

0.080

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.84

T;T;T;.;T

MetaRNN

Benign

0.0098

T;T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.1

L;L;.;L;L

MutationTaster

Benign

0.98

D;D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.3

N;N;N;N;N

REVEL

Benign

0.28

Sift

Benign

0.49

T;T;T;T;T

Sift4G

Benign

0.84

T;T;T;T;T

Polyphen

0.83

P;B;.;B;B

Vest4

0.70

MVP

0.73

MPC

0.15

ClinPred

0.016

GERP RS

4.3

Varity_R

0.19

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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