rs2646265

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004369.4(COL6A3):c.6945C>T(p.Phe2315Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,603,108 control chromosomes in the GnomAD database, including 9,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 917 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8392 hom. )

Consequence

COL6A3
NM_004369.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.965

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 2-237348370-G-A is Benign according to our data. Variant chr2-237348370-G-A is described in ClinVar as [Benign]. Clinvar id is 94975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237348370-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.965 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4 link	c.6945C>T	p.Phe2315Phe	synonymous_variant	Exon 30 of 44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3	NM_057167.4 link	c.6327C>T	p.Phe2109Phe	synonymous_variant	Exon 29 of 43		NP_476508.2	P12111-2Q8N4Z1Q63HQ4
COL6A3	NM_057166.5 link	c.5124C>T	p.Phe1708Phe	synonymous_variant	Exon 27 of 41		NP_476507.3	P12111-4B7ZW00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL6A3	ENST00000295550.9 link	c.6945C>T	p.Phe2315Phe	synonymous_variant	Exon 30 of 44	1	NM_004369.4	ENSP00000295550.4	P12111-1
COL6A3	ENST00000472056.5 link	c.5124C>T	p.Phe1708Phe	synonymous_variant	Exon 27 of 41	1		ENSP00000418285.1	P12111-4
COL6A3	ENST00000353578.9 link	c.6327C>T	p.Phe2109Phe	synonymous_variant	Exon 29 of 43	5		ENSP00000315873.4	P12111-2
COL6A3	ENST00000491769.1 link	n.1199C>T		non_coding_transcript_exon_variant	Exon 7 of 20	5

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16247

AN:

152080

Hom.:

917

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0899

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.162

Gnomad ASJ

AF:

0.134

Gnomad EAS

AF:

0.0487

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.120

GnomAD3 exomes

AF:

0.114

AC:

28654

AN:

250870

Hom.:

1756

AF XY:

0.114

AC XY:

15455

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.0883

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.128

Gnomad EAS exome

AF:

0.0470

Gnomad SAS exome

AF:

0.120

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.105

AC:

151968

AN:

1450910

Hom.:

8392

Cov.:

AF XY:

0.105

AC XY:

76127

AN XY:

722574

show subpopulations

Gnomad4 AFR exome

AF:

0.0894

Gnomad4 AMR exome

AF:

0.171

Gnomad4 ASJ exome

AF:

0.123

Gnomad4 EAS exome

AF:

0.0518

Gnomad4 SAS exome

AF:

0.119

Gnomad4 FIN exome

AF:

0.113

Gnomad4 NFE exome

AF:

0.102

Gnomad4 OTH exome

AF:

0.103

GnomAD4 genome

AF:

0.107

AC:

16254

AN:

152198

Hom.:

917

Cov.:

AF XY:

0.109

AC XY:

8143

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0898

Gnomad4 AMR

AF:

0.163

Gnomad4 ASJ

AF:

0.134

Gnomad4 EAS

AF:

0.0487

Gnomad4 SAS

AF:

0.118

Gnomad4 FIN

AF:

0.114

Gnomad4 NFE

AF:

0.105

Gnomad4 OTH

AF:

0.118

Alfa

AF:

0.109

Hom.:

2178

Bravo

AF:

0.108

Asia WGS

AF:

0.0800

AC:

280

AN:

3478

EpiCase

AF:

0.114

EpiControl

AF:

0.110

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 31, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 37% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 34. Only high quality variants are reported. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Bethlem myopathy 1A

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Collagen 6-related myopathy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

5.6

DANN

Benign

0.72

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