dbSNP rs116729313: COL6A3:p.Ile244Val (chr2-237388164-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004369.4(COL6A3):c.730A>G(p.Ile244Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000535 in 1,614,036 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 3 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.735

Publications

3 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: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
collagen 6-related myopathy
Inheritance: AD, AR 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: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
Ullrich congenital muscular dystrophy 1A
Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011121392).

BP6

Variant 2-237388164-T-C is Benign according to our data. Variant chr2-237388164-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94984.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00248 (377/152264) while in subpopulation AFR AF = 0.00835 (347/41550). AF 95% confidence interval is 0.00763. There are 0 homozygotes in GnomAd4. There are 186 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 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
COL6A3	NM_004369.4	MANE Select	c.730A>G	p.Ile244Val	missense	Exon 4 of 44	NP_004360.2
COL6A3	NM_057167.4		c.112A>G	p.Ile38Val	missense	Exon 3 of 43	NP_476508.2
COL6A3	NM_057165.5		c.112A>G	p.Ile38Val	missense	Exon 3 of 8	NP_476506.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.730A>G	p.Ile244Val	missense	Exon 4 of 44	ENSP00000295550.4
COL6A3	ENST00000392004.7	TSL:1	c.112A>G	p.Ile38Val	missense	Exon 3 of 8	ENSP00000375861.3
COL6A3	ENST00000433762.1	TSL:1	c.730A>G	p.Ile244Val	missense	Exon 4 of 6	ENSP00000389539.1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00838

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000760

AC:

188

AN:

247526

AF XY:

0.000655

show subpopulations

Gnomad AFR exome

AF:

0.00856

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.000659

GnomAD4 exome

AF:

0.000332

AC:

486

AN:

1461772

Hom.:

Cov.:

AF XY:

0.000304

AC XY:

221

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.00893

AC:

299

AN:

33480

American (AMR)

AF:

0.000961

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000962

AC:

107

AN:

1112010

Other (OTH)

AF:

0.000513

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

108

135

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:

0.00248

AC:

377

AN:

152264

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00835

AC:

347

AN:

41550

American (AMR)

AF:

0.00111

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68014

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00103

Hom.:

Bravo

AF:

0.00271

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000898

AC:

109

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Bethlem myopathy 1A (1)

Collagen 6-related myopathy (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.16

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.72

M_CAP

Benign

0.032

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.75

MutationAssessor

Benign

-0.24

PhyloP100

0.73

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.090

REVEL

Benign

0.27

Sift

Benign

0.69

Sift4G

Benign

0.38

Polyphen

0.65

Vest4

0.17

MVP

0.51

MPC

0.19

ClinPred

0.0096

GERP RS

4.3

Varity_R

0.033

gMVP

0.12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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