dbSNP rs111402193: COL6A3:p.Val342Met (chr2-237387870-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004369.4(COL6A3):c.1024G>A(p.Val342Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000633 in 1,614,116 control chromosomes in the GnomAD database, including 9 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00081 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00061 ( 7 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:6

Conservation

PhyloP100: 1.70

Publications

6 publications found

Variant links:

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

COL6A3 Gene-Disease associations (from GenCC):

Bethlem myopathy 1A
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
collagen 6-related myopathy
Inheritance: AR, SD, AD Classification: DEFINITIVE Submitted by: ClinGen
Ullrich congenital muscular dystrophy 1C
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
dystonia 27
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, Illumina
Ullrich congenital muscular dystrophy 1A
Inheritance: AR, AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013223261).

BP6

Variant 2-237387870-C-T is Benign according to our data. Variant chr2-237387870-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000807 (123/152328) while in subpopulation AMR AF = 0.00398 (61/15310). AF 95% confidence interval is 0.00318. There are 2 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL6A3	NM_004369.4	MANE Select	c.1024G>A	p.Val342Met	missense	Exon 4 of 44	NP_004360.2	D9ZGF2
COL6A3	NM_057167.4		c.406G>A	p.Val136Met	missense	Exon 3 of 43	NP_476508.2	P12111-2
COL6A3	NM_057165.5		c.406G>A	p.Val136Met	missense	Exon 3 of 8	NP_476506.3	P12111-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.1024G>A	p.Val342Met	missense	Exon 4 of 44	ENSP00000295550.4	P12111-1
COL6A3	ENST00000392004.7	TSL:1	c.406G>A	p.Val136Met	missense	Exon 3 of 8	ENSP00000375861.3	P12111-5
COL6A3	ENST00000433762.1	TSL:1	c.1024G>A	p.Val342Met	missense	Exon 4 of 6	ENSP00000389539.1	C9JNG9

Frequencies

GnomAD3 genomes

AF:

0.000815

AC:

124

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000769

AC:

193

AN:

250856

AF XY:

0.000671

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000984

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.000706

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000614

AC:

898

AN:

1461788

Hom.:

Cov.:

AF XY:

0.000623

AC XY:

453

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33476

American (AMR)

AF:

0.00112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00256

AC:

AN:

26132

East Asian (EAS)

AF:

0.000202

AC:

AN:

39694

South Asian (SAS)

AF:

0.000464

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.000749

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.0140

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000480

AC:

534

AN:

1111976

Other (OTH)

AF:

0.000894

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000807

AC:

123

AN:

152328

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41578

American (AMR)

AF:

0.00398

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00124

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000367

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.000866

Hom.:

Bravo

AF:

0.00108

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000708

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Bethlem myopathy 1A (1)

COL6A3-related disorder (1)

Collagen 6-related myopathy (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.0

PhyloP100

1.7

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.58

REVEL

Benign

0.27

Sift

Benign

0.059

Sift4G

Uncertain

0.036

Polyphen

1.0

Vest4

0.25

MVP

0.81

MPC

0.63

ClinPred

0.023

GERP RS

5.2

Varity_R

0.050

gMVP

0.28

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over