rs36117715

chr2-237353378-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):c.6653C>T(p.Pro2218Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,613,906 control chromosomes in the GnomAD database, including 2,181 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. P2218P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.072 (713 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1468 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.355

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=0.0039197206).
• BP6: Variant 2-237353378-G-A is Benign according to our data. Variant chr2-237353378-G-A is described in ClinVar as [Benign]. Clinvar id is 94967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237353378-G-A is described in Lovd as [Benign]. Variant chr2-237353378-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.6653C>T	p.Pro2218Leu	missense_variant	25/44	ENST00000295550.9
COL6A3	NM_057167.4	c.6035C>T	p.Pro2012Leu	missense_variant	24/43
COL6A3	NM_057166.5	c.4832C>T	p.Pro1611Leu	missense_variant	22/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.6653C>T	p.Pro2218Leu	missense_variant	25/44	1	NM_004369.4	P1
COL6A3	ENST00000472056.5	c.4832C>T	p.Pro1611Leu	missense_variant	22/41	1
COL6A3	ENST00000353578.9	c.6035C>T	p.Pro2012Leu	missense_variant	24/43	5
COL6A3	ENST00000491769.1	n.907C>T		non_coding_transcript_exon_variant	2/20	5

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10936 AN: 152076 Hom.: 713 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0420

Gnomad ASJ AF: 0.0936

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0328

Gnomad OTH AF: 0.0744

GnomAD3 exomes AF: 0.0418 AC: 10515 AN: 251404 Hom.: 482 AF XY: 0.0396 AC XY: 5378 AN XY: 135872

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.0297

Gnomad ASJ exome AF: 0.0911

Gnomad EAS exome AF: 0.00457

Gnomad SAS exome AF: 0.0333

Gnomad FIN exome AF: 0.00879

Gnomad NFE exome AF: 0.0350

Gnomad OTH exome AF: 0.0446

GnomAD4 exome AF: 0.0348 AC: 50855 AN: 1461712 Hom.: 1468 Cov.: 32 AF XY: 0.0346 AC XY: 25136 AN XY: 727194

Gnomad4 AFR exome AF: 0.182

Gnomad4 AMR exome AF: 0.0310

Gnomad4 ASJ exome AF: 0.0898

Gnomad4 EAS exome AF: 0.00353

Gnomad4 SAS exome AF: 0.0338

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.0307

Gnomad4 OTH exome AF: 0.0453

GnomAD4 genome AF: 0.0719 AC: 10948 AN: 152194 Hom.: 713 Cov.: 32 AF XY: 0.0688 AC XY: 5123 AN XY: 74412

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.0418

Gnomad4 ASJ AF: 0.0936

Gnomad4 EAS AF: 0.00501

Gnomad4 SAS AF: 0.0314

Gnomad4 FIN AF: 0.00904

Gnomad4 NFE AF: 0.0328

Gnomad4 OTH AF: 0.0736

Alfa AF: 0.0432 Hom.: 449

Bravo AF: 0.0801

TwinsUK AF: 0.0297 AC: 110

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.173 AC: 761

ESP6500EA AF: 0.0371 AC: 319

ExAC AF: 0.0454 AC: 5508

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.0371

EpiControl AF: 0.0427

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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 23, 2017

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	13
Dann	Benign	0.39
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.86	D;D;D;D;.
MetaRNN	Benign	0.0039	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	D;D;D;.;D
REVEL	Benign	0.24
Sift	Benign	0.37	T;T;T;.;T
Sift4G	Uncertain	0.014	D;D;D;D;D
Polyphen		0.017	B;B;.;.;B
Vest4		0.13
MPC		0.15
ClinPred		0.010	T
GERP RS		-1.3
Varity_R		0.059
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs36117715; hg19: chr2-238262021; COSMIC: COSV55082067; COSMIC: COSV55082067;