chr2-237387663-G-C

Variant names:

• chr2-237387663-G-C
• rs113716915
• NM_004369.4:c.1231C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004369.4(COL6A3):​c.1231C>G​(p.Leu411Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,613,786 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (37 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.51
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010365635).
• BP6: Variant 2-237387663-G-C is Benign according to our data. Variant chr2-237387663-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00383 (584/152300) while in subpopulation NFE AF = 0.0054 (367/68014). AF 95% confidence interval is 0.00494. There are 2 homozygotes in GnomAd4. There are 277 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,SD gene

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.1231C>G	p.Leu411Val	missense	Exon 4 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.613C>G	p.Leu205Val	missense	Exon 3 of 43	NP_476508.2
	COL6A3	NM_057165.5		c.613C>G	p.Leu205Val	missense	Exon 3 of 8	NP_476506.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.1231C>G	p.Leu411Val	missense	Exon 4 of 44	ENSP00000295550.4
	COL6A3	ENST00000392004.7	TSL:1	c.613C>G	p.Leu205Val	missense	Exon 3 of 8	ENSP00000375861.3
	COL6A3	ENST00000433762.1	TSL:1	c.1231C>G	p.Leu411Val	missense	Exon 4 of 6	ENSP00000389539.1

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 584 AN: 152182 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00540

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00396 AC: 991 AN: 250414 AF XY: 0.00412

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00552

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00551 AC: 8053 AN: 1461486 Hom.: 37 Cov.: 32 AF XY: 0.00535 AC XY: 3887 AN XY: 726994

African (AFR) AF: 0.00111 AC: 37 AN: 33474

American (AMR) AF: 0.00201 AC: 90 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 440 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00122 AC: 105 AN: 86166

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53392

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

European-Non Finnish (NFE) AF: 0.00627 AC: 6970 AN: 1111830

Other (OTH) AF: 0.00576 AC: 348 AN: 60378

GnomAD4 genome AF: 0.00383 AC: 584 AN: 152300 Hom.: 2 Cov.: 33 AF XY: 0.00372 AC XY: 277 AN XY: 74468

African (AFR) AF: 0.00132 AC: 55 AN: 41572

American (AMR) AF: 0.00431 AC: 66 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00540 AC: 367 AN: 68014

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00626 Hom.: 4

Bravo AF: 0.00377

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00359 AC: 436

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00548

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2018

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.

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 05, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL6A3: BP4, BS2

Bethlem myopathy 1A Benign:1

Jan 30, 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 12, 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	0.081
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.22
Sift	Benign	0.22	T
Sift4G	Benign	0.29	T
Polyphen		0.30	B
Vest4		0.11
MVP		0.74
MPC		0.35
ClinPred		0.0073	T
GERP RS		1.8
Varity_R		0.071
gMVP		0.31
Mutation Taster		=91/9	polymorphism

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: rs113716915; hg19: chr2-238296306;