rs200200671

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001849.4(COL6A2):c.2927T>C(p.Leu976Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,607,566 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. L976L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.82

Publications

6 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17084661).

BP6

Variant 21-46132419-T-C is Benign according to our data. Variant chr21-46132419-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476480.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4 link	c.2927T>C	p.Leu976Ser	missense_variant	Exon 28 of 28	ENST00000300527.9	NP_001840.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 link	c.2927T>C	p.Leu976Ser	missense_variant	Exon 28 of 28	1	NM_001849.4	ENSP00000300527.4

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000213

AC:

AN:

244680

AF XY:

0.000195

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.000154

Gnomad NFE exome

AF:

0.000209

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000221

AC:

322

AN:

1455228

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

152

AN XY:

723434

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33402

American (AMR)

AF:

0.0000896

AC:

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00339

AC:

134

AN:

39578

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.000280

AC:

AN:

49990

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000150

AC:

166

AN:

1109402

Other (OTH)

AF:

0.0000499

AC:

AN:

60162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

117

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:

0.000190

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00174

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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:

0.000397

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.000239

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

May 08, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Sep 21, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bethlem myopathy 1A

Benign:1

Nov 28, 2024

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

Pathogenic

0.60

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.35

Eigen

Benign

0.010

Eigen_PC

Benign

0.075

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.17

MetaSVM

Uncertain

-0.057

MutationAssessor

Benign

1.6

PhyloP100

7.8

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.63

Sift

Benign

0.061

Sift4G

Uncertain

0.0060

Polyphen

0.21

Vest4

0.36

MVP

0.97

MPC

0.49

ClinPred

0.098

GERP RS

4.4

Varity_R

0.14

gMVP

0.94

Mutation Taster

=62/38

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