rs111595697

chr2-237340988-G-Achr2-237340988-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004369.4(COL6A3):c.7928C>T(p.Ala2643Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,614,164 control chromosomes in the GnomAD database, including 20 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2643S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (12 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.82

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00923264).
• BP6: Variant 2-237340988-G-A is Benign according to our data. Variant chr2-237340988-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237340988-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0045 (685/152288) while in subpopulation AFR AF= 0.0136 (565/41560). AF 95% confidence interval is 0.0127. There are 8 homozygotes in gnomad4. There are 321 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.7928C>T	p.Ala2643Val	missense_variant	38/44	ENST00000295550.9
COL6A3	NM_057167.4	c.7310C>T	p.Ala2437Val	missense_variant	37/43
COL6A3	NM_057166.5	c.6107C>T	p.Ala2036Val	missense_variant	35/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.7928C>T	p.Ala2643Val	missense_variant	38/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.00444 AC: 676 AN: 152170 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00192 AC: 483 AN: 250964 Hom.: 6 AF XY: 0.00155 AC XY: 210 AN XY: 135622

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00135 AC: 1977 AN: 1461876 Hom.: 12 Cov.: 35 AF XY: 0.00125 AC XY: 909 AN XY: 727242

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00450 AC: 685 AN: 152288 Hom.: 8 Cov.: 31 AF XY: 0.00431 AC XY: 321 AN XY: 74450

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00193 Hom.: 1

Bravo AF: 0.00475

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00222 AC: 269

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2017	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. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	COL6A3: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 19, 2017

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	16
Dann	Benign	0.80
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.87	D;D;D;D;.
MetaRNN	Benign	0.0092	T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.041	D;T;T;T;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.52	P;D;.;.;P
Vest4		0.22
MVP		0.81
MPC		0.15
ClinPred		0.014	T
GERP RS		-3.2
Varity_R		0.075
gMVP		0.39

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

Other links and lift over

dbSNP: rs111595697; hg19: chr2-238249631;