rs765430501

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001849.4(COL6A2):c.1288G>A(p.Gly430Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,563,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.20

Publications

1 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: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL6A2	NM_001849.4 link	c.1288G>A	p.Gly430Ser	missense_variant	Exon 15 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3 link	c.1288G>A	p.Gly430Ser	missense_variant	Exon 15 of 28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3 link	c.1288G>A	p.Gly430Ser	missense_variant	Exon 15 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL6A2	ENST00000300527.9 link	c.1288G>A	p.Gly430Ser	missense_variant	Exon 15 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6 link	c.1288G>A	p.Gly430Ser	missense_variant	Exon 15 of 28	5	NM_058174.3	ENSP00000380870.1
COL6A2	ENST00000409416.6 link	c.1288G>A	p.Gly430Ser	missense_variant	Exon 14 of 27	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000229

AC:

AN:

174532

AF XY:

0.0000324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000386

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000624

Gnomad NFE exome

AF:

0.0000282

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000156

AC:

AN:

1411950

Hom.:

Cov.:

AF XY:

0.0000172

AC XY:

AN XY:

697422

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32818

American (AMR)

AF:

0.0000272

AC:

AN:

36820

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25224

East Asian (EAS)

AF:

0.0000530

AC:

AN:

37744

South Asian (SAS)

AF:

0.00

AC:

AN:

80284

European-Finnish (FIN)

AF:

0.0000205

AC:

AN:

48862

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

1085982

Other (OTH)

AF:

0.0000342

AC:

AN:

58526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.0000329

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67998

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.0000847

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000878

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Aug 22, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Replaces the glycine in the canonical Gly-X-Y repeat of the triple helical domain and is expected to disrupt normal protein folding and function, which is an established mechanism of disease (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jun 18, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bethlem myopathy 1A

Uncertain:1

May 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant disrupts the triple helix domain of COL6A2. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL6A2, missense variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL6A2 protein function. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 430 of the COL6A2 protein (p.Gly430Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 289769). -

COL6A2-related disorder

Uncertain:1

May 17, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL6A2 c.1288G>A variant is predicted to result in the amino acid substitution p.Gly430Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0051% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-47539720-G-A). This variant affects a Gly residue of the conserved triple helical domain, where substitutions of the glycine are frequently pathogenic (Butterfield et al. 2013. PubMed ID: 24038877). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;.;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.8

H;H;H;H

PhyloP100

6.2

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-4.2

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.96

MutPred

0.92

Gain of phosphorylation at G430 (P = 0.0022);Gain of phosphorylation at G430 (P = 0.0022);Gain of phosphorylation at G430 (P = 0.0022);Gain of phosphorylation at G430 (P = 0.0022);

MVP

0.99

MPC

0.61

ClinPred

0.99

GERP RS

4.9

Varity_R

0.49

gMVP

0.78

Mutation Taster

=37/63

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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