chr21-46132478-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_001849.4(COL6A2):c.2986G>A(p.Val996Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,606,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V996V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.746

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Ullrich congenital muscular dystrophy 1B
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
Bethlem myopathy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
Ullrich congenital muscular dystrophy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myosclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

COL6A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34026134).

BP6

Variant 21-46132478-G-A is Benign according to our data. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387. Variant chr21-46132478-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 340387.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4 link	c.2986G>A	p.Val996Met	missense_variant	Exon 28 of 28	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 link	c.2986G>A	p.Val996Met	missense_variant	Exon 28 of 28	1	NM_001849.4	ENSP00000300527.4		P12110-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000625

AC:

AN:

240122

AF XY:

0.0000686

show subpopulations

Gnomad AFR exome

AF:

0.000381

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000840

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1454488

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

723356

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39598

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48672

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000126

AC:

140

AN:

1110040

Other (OTH)

AF:

0.000133

AC:

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.000193

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000826

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2986G>A (p.V996M) alteration is located in exon 28 (coding exon 27) of the COL6A2 gene. This alteration results from a G to A substitution at nucleotide position 2986, causing the valine (V) at amino acid position 996 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Myosclerosis

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Collagen 6-related myopathy

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Bethlem myopathy 1A

Benign:1

Nov 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.1

PhyloP100

0.75

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.37

REVEL

Uncertain

0.35

Sift

Benign

0.084

Sift4G

Benign

0.10

Polyphen

0.96

Vest4

0.22

MVP

0.84

MPC

0.42

ClinPred

0.13

GERP RS

-0.21

Varity_R

0.026

gMVP

0.77

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over