2-237347864-G-T

Position:

chr2-237347864-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000295550.9(COL6A3):c.6972C>A(p.Asn2324Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000087 in 1,609,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N2324N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

COL6A3
ENST00000295550.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -0.684

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.065580994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A3	NM_004369.4 linkuse as main transcript	c.6972C>A	p.Asn2324Lys	missense_variant	31/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4 linkuse as main transcript	c.6354C>A	p.Asn2118Lys	missense_variant	30/43		NP_476508.2
COL6A3	NM_057166.5 linkuse as main transcript	c.5151C>A	p.Asn1717Lys	missense_variant	28/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.6972C>A	p.Asn2324Lys	missense_variant	31/44	1	NM_004369.4	ENSP00000295550	P1	P12111-1
COL6A3	ENST00000472056.5 linkuse as main transcript	c.5151C>A	p.Asn1717Lys	missense_variant	28/41	1		ENSP00000418285		P12111-4
COL6A3	ENST00000353578.9 linkuse as main transcript	c.6354C>A	p.Asn2118Lys	missense_variant	30/43	5		ENSP00000315873		P12111-2
COL6A3	ENST00000491769.1 linkuse as main transcript	n.1226C>A		non_coding_transcript_exon_variant	8/20	5

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1457518

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724338

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000226

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:

0.00

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000589

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

Bravo

AF:

0.000162

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 04, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 10, 2020	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2022

The c.6972C>A (p.N2324K) alteration is located in exon 31 (coding exon 30) of the COL6A3 gene. This alteration results from a C to A substitution at nucleotide position 6972, causing the asparagine (N) at amino acid position 2324 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Bethlem myopathy 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2324 of the COL6A3 protein (p.Asn2324Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL6A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 597010). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL6A3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.33

DANN

Benign

0.91

DEOGEN2

Benign

0.14

.;T;.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.67

T;T;T;T;.

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.066

T;T;T;T;T

MetaSVM

Benign

-0.28

MutationAssessor

Benign

0.17

.;N;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.36

N;N;N;.;N

REVEL

Benign

0.11

Sift

Benign

0.67

T;T;T;.;T

Sift4G

Benign

0.78

T;T;T;T;T

Polyphen

0.0080

B;P;.;.;B

Vest4

0.21

MutPred

0.41

.;Gain of methylation at N2324 (P = 0.0024);.;.;.;

MVP

0.52

MPC

0.17

ClinPred

0.037

GERP RS

-1.8

Varity_R

0.060

gMVP

0.085

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