2-237371833-C-T

Variant names:

• chr2-237371833-C-T
• rs80272723
• NM_004369.4:c.4184G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_004369.4(COL6A3):​c.4184G>A​(p.Arg1395Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,613,540 control chromosomes in the GnomAD database, including 170 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1395W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (157 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.596
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1C

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020683706).
• BP6: Variant 2-237371833-C-T is Benign according to our data. Variant chr2-237371833-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94929.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	NM_004369.4	MANE Select	c.4184G>A	p.Arg1395Gln	missense	Exon 9 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.3566G>A	p.Arg1189Gln	missense	Exon 8 of 43	NP_476508.2
	COL6A3	NM_057166.5		c.2363G>A	p.Arg788Gln	missense	Exon 6 of 41	NP_476507.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.4184G>A	p.Arg1395Gln	missense	Exon 9 of 44	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.2363G>A	p.Arg788Gln	missense	Exon 6 of 41	ENSP00000418285.1
	COL6A3	ENST00000392004.7	TSL:1	c.3566G>A	p.Arg1189Gln	missense	Exon 8 of 8	ENSP00000375861.3

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 672 AN: 151966 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00813

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0783

Gnomad SAS AF: 0.00418

Gnomad FIN AF: 0.00519

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.0100 AC: 2511 AN: 251046 AF XY: 0.00890

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0730

Gnomad FIN exome AF: 0.00549

Gnomad NFE exome AF: 0.000748

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00358 AC: 5227 AN: 1461456 Hom.: 157 Cov.: 31 AF XY: 0.00347 AC XY: 2523 AN XY: 726996

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.0223 AC: 998 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.0757 AC: 3007 AN: 39700

South Asian (SAS) AF: 0.00241 AC: 208 AN: 86258

European-Finnish (FIN) AF: 0.00713 AC: 378 AN: 52990

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.000325 AC: 361 AN: 1112006

Other (OTH) AF: 0.00414 AC: 250 AN: 60394

GnomAD4 genome AF: 0.00439 AC: 668 AN: 152084 Hom.: 13 Cov.: 32 AF XY: 0.00491 AC XY: 365 AN XY: 74312

African (AFR) AF: 0.000626 AC: 26 AN: 41508

American (AMR) AF: 0.00805 AC: 123 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0779 AC: 400 AN: 5132

South Asian (SAS) AF: 0.00418 AC: 20 AN: 4784

European-Finnish (FIN) AF: 0.00519 AC: 55 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 67994

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00380 Hom.: 39

Bravo AF: 0.00548

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00920 AC: 1117

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Dec 19, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 23, 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.

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.

not provided Benign:2

Nov 03, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dystonia 27 Uncertain:1

Oct 22, 2022

Department of Neurology, Xijing Hospital, Fourth Military Medical University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ullrich congenital muscular dystrophy 1A;C4225336:Dystonia 27;CN029274:Bethlem myopathy 1A Benign:1

Aug 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bethlem myopathy 1A Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Collagen 6-related myopathy Benign:1

Mar 06, 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.60
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.26
Sift	Benign	0.36	T
Sift4G	Benign	0.67	T
Polyphen		0.93	P
Vest4		0.21
MVP		0.84
MPC		0.49
ClinPred		0.017	T
GERP RS		4.8
PromoterAI		-0.097	Neutral
Varity_R		0.080
gMVP		0.33
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs80272723; hg19: chr2-238280476; COSMIC: COSV55083723;