rs112928650

Positions:

chr2-237336365-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004369.4(COL6A3):c.8735C>T(p.Pro2912Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,148 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2912P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0044 ( 17 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 61 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.63

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002975285).

BP6

Variant 2-237336365-G-A is Benign according to our data. Variant chr2-237336365-G-A is described in ClinVar as [Benign]. Clinvar id is 166936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237336365-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0044 (670/152324) while in subpopulation EAS AF= 0.0328 (170/5188). AF 95% confidence interval is 0.0287. There are 17 homozygotes in gnomad4. There are 465 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A3	NM_004369.4 linkuse as main transcript	c.8735C>T	p.Pro2912Leu	missense_variant	40/44	ENST00000295550.9
COL6A3	NM_057167.4 linkuse as main transcript	c.8117C>T	p.Pro2706Leu	missense_variant	39/43
COL6A3	NM_057166.5 linkuse as main transcript	c.6914C>T	p.Pro2305Leu	missense_variant	37/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.8735C>T	p.Pro2912Leu	missense_variant	40/44	1	NM_004369.4	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.00440

AC:

669

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0325

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0396

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00613

AC:

1542

AN:

251362

Hom.:

AF XY:

0.00603

AC XY:

820

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.000432

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0319

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.0333

Gnomad NFE exome

AF:

0.00136

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00260

AC:

3801

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

1858

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0317

Gnomad4 SAS exome

AF:

0.000846

Gnomad4 FIN exome

AF:

0.0319

Gnomad4 NFE exome

AF:

0.000498

Gnomad4 OTH exome

AF:

0.00313

GnomAD4 genome

AF:

0.00440

AC:

670

AN:

152324

Hom.:

Cov.:

AF XY:

0.00624

AC XY:

465

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0328

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0396

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00187

Hom.:

Bravo

AF:

0.00193

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00589

AC:

714

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 26, 2013	- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.37

DEOGEN2

Benign

0.23

.;T;.;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.23

LIST_S2

Uncertain

0.87

D;D;D;D;.

MetaRNN

Benign

0.0030

T;T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Uncertain

2.7

.;M;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.6

N;N;N;.;N

REVEL

Benign

0.19

Sift

Benign

0.039

D;T;D;.;D

Sift4G

Benign

0.19

T;T;T;T;T

Polyphen

1.0

D;D;.;.;D

Vest4

0.19

MVP

0.86

MPC

0.15

ClinPred

0.023

GERP RS

0.76

Varity_R

0.048

gMVP

0.086

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