21-46120518-G-A

Position:

chr21-46120518-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_001849.4(COL6A2):c.1336G>A(p.Asp446Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000881 in 1,507,332 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00092 ( 1 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:4O:1

Conservation

PhyloP100: 6.86

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 Likely_benign. Variant got -1 ACMG points.

BP6

Variant 21-46120518-G-A is Benign according to our data. Variant chr21-46120518-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194621.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=3, not_provided=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4 link	c.1336G>A	p.Asp446Asn	missense_variant	16/28	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 link	c.1336G>A	p.Asp446Asn	missense_variant	16/28		NP_478054.2	P12110-2
COL6A2	NM_058175.3 link	c.1336G>A	p.Asp446Asn	missense_variant	16/28		NP_478055.2	P12110-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL6A2	ENST00000300527.9 link	c.1336G>A	p.Asp446Asn	missense_variant	16/28	1	NM_001849.4	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6 link	c.1336G>A	p.Asp446Asn	missense_variant	16/28	5		ENSP00000380870.1	P12110-2
COL6A2	ENST00000409416.6 link	c.1336G>A	p.Asp446Asn	missense_variant	15/27	5		ENSP00000387115.1	P12110-3
COL6A2	ENST00000413758.1 link	c.-42G>A		upstream_gene_variant		3		ENSP00000395751.1	H7C0M5

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000418

AC:

AN:

107528

Hom.:

AF XY:

0.000404

AC XY:

AN XY:

56958

show subpopulations

Gnomad AFR exome

AF:

0.000145

Gnomad AMR exome

AF:

0.0000663

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000751

Gnomad NFE exome

AF:

0.000815

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000916

AC:

1241

AN:

1355156

Hom.:

Cov.:

AF XY:

0.000884

AC XY:

590

AN XY:

667224

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000777

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000642

Gnomad4 NFE exome

AF:

0.00112

Gnomad4 OTH exome

AF:

0.000305

GnomAD4 genome

AF:

0.000572

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000446

ExAC

AF:

0.0000966

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 30, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2024	Reported previously as a variant of uncertain clinical significance in multiple individuals with limb-girdle muscular dystrophy in published literature (PMID: 27854218, 30564623); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30564623, 23040494, 27854218, 31127727) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	research	Center for Genetic Medicine Research, Children's National Medical Center	Dec 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 25, 2016	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2015

- -

Ullrich congenital muscular dystrophy 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Feb 16, 2023

This sequence variant is a single nucleotide substitution (G>A) at coding position 1336 of the COL6A2 gene that results in an aspartic acid to asparagine amino acid change at residue 446 of the COL6A2 protein. The Asp446 residue falls in the triple helical domain which plays a critical role in the proper assembly of collagen VI (PMID: 20301676). This is a previously reported variant (ClinVar) that has been reported in a study of individuals affected by a myopathy (PMID:27854218). This variant is present in 60 of 138,852 (0.04%) alleles in the gnomAD population database. Multiple bioinformatic tools predict that this aspartic acid to asparagine amino acid change would be damaging, and the aspartic acid residue is highly conserved at this position across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PP3 -

Myosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

- -

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;CN029274:Bethlem myopathy 1A;CN117976:Collagen 6-related myopathy

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 05-08-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

T;.;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;.;D

M_CAP

Pathogenic

0.72

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Pathogenic

0.81

MutationAssessor

Benign

1.6

L;L;L;L

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Uncertain

0.59

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Uncertain

0.041

D;T;T;D

Polyphen

1.0

D;D;D;D

Vest4

0.44

MVP

0.97

MPC

0.15

ClinPred

0.27

GERP RS

4.4

Varity_R

0.19

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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