rs750063736

Positions:

chr2-237361778-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6

The ENST00000295550.9(COL6A3):c.6117G>C(p.Gln2039His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

COL6A3
ENST00000295550.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.08

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in ENST00000295550.9

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22710958).

BP6

Variant 2-237361778-C-G is Benign according to our data. Variant chr2-237361778-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476544.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A3	NM_004369.4 linkuse as main transcript	c.6117G>C	p.Gln2039His	missense_variant	15/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4 linkuse as main transcript	c.5499G>C	p.Gln1833His	missense_variant	14/43		NP_476508.2
COL6A3	NM_057166.5 linkuse as main transcript	c.4296G>C	p.Gln1432His	missense_variant	12/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.6117G>C	p.Gln2039His	missense_variant	15/44	1	NM_004369.4	ENSP00000295550	P1	P12111-1
COL6A3	ENST00000472056.5 linkuse as main transcript	c.4296G>C	p.Gln1432His	missense_variant	12/41	1		ENSP00000418285		P12111-4
COL6A3	ENST00000353578.9 linkuse as main transcript	c.5499G>C	p.Gln1833His	missense_variant	14/43	5		ENSP00000315873		P12111-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251484

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000308

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 13, 2023

- -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.27

CADD

Benign

6.8

DANN

Benign

0.74

DEOGEN2

Uncertain

0.46

.;T;.;T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.82

T;T;T;T;.

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.23

T;T;T;T;T

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

0.34

.;N;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.9

N;N;N;.;N

REVEL

Uncertain

0.40

Sift

Benign

0.15

T;T;D;.;T

Sift4G

Uncertain

0.0050

D;D;D;D;D

Polyphen

1.0

D;B;.;.;D

Vest4

0.41

MutPred

0.35

.;Loss of ubiquitination at K2035 (P = 0.0877);.;.;.;

MVP

0.81

MPC

0.31

ClinPred

0.13

GERP RS

-7.4

Varity_R

0.10

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over