2-237336320-A-G

Variant names:

• chr2-237336320-A-G
• rs6728818
• NM_004369.4:c.8780T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.8780T>C​(p.Met2927Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 1,613,978 control chromosomes in the GnomAD database, including 333,844 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2927I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.68 (35488 hom., cov: 33)
  • Exomes 𝑓: 0.64 (298356 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.38
• Publications: 36 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=1.2549137E-6).
• BP6: Variant 2-237336320-A-G is Benign according to our data. Variant chr2-237336320-A-G is described in ClinVar as Benign. ClinVar VariationId is 95008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.8780T>C	p.Met2927Thr	missense_variant	Exon 40 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.8162T>C	p.Met2721Thr	missense_variant	Exon 39 of 43		NP_476508.2
COL6A3	NM_057166.5	c.6959T>C	p.Met2320Thr	missense_variant	Exon 37 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.8780T>C	p.Met2927Thr	missense_variant	Exon 40 of 44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes AF: 0.678 AC: 103129 AN: 152028 Hom.: 35463 Cov.: 33

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.694

GnomAD2 exomes AF: 0.631 AC: 158412 AN: 251020 AF XY: 0.632

Gnomad AFR exome AF: 0.782

Gnomad AMR exome AF: 0.524

Gnomad ASJ exome AF: 0.724

Gnomad EAS exome AF: 0.532

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.653

Gnomad OTH exome AF: 0.660

GnomAD4 exome AF: 0.636 AC: 930432 AN: 1461832 Hom.: 298356 Cov.: 78 AF XY: 0.634 AC XY: 461244 AN XY: 727218

African (AFR) AF: 0.788 AC: 26369 AN: 33480

American (AMR) AF: 0.534 AC: 23873 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 19101 AN: 26136

East Asian (EAS) AF: 0.567 AC: 22526 AN: 39700

South Asian (SAS) AF: 0.554 AC: 47779 AN: 86258

European-Finnish (FIN) AF: 0.705 AC: 37659 AN: 53380

Middle Eastern (MID) AF: 0.735 AC: 4238 AN: 5768

European-Non Finnish (NFE) AF: 0.638 AC: 709951 AN: 1111990

Other (OTH) AF: 0.645 AC: 38936 AN: 60396

GnomAD4 genome AF: 0.678 AC: 103196 AN: 152146 Hom.: 35488 Cov.: 33 AF XY: 0.678 AC XY: 50390 AN XY: 74374

African (AFR) AF: 0.778 AC: 32322 AN: 41522

American (AMR) AF: 0.591 AC: 9037 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2560 AN: 3468

East Asian (EAS) AF: 0.536 AC: 2770 AN: 5164

South Asian (SAS) AF: 0.548 AC: 2638 AN: 4812

European-Finnish (FIN) AF: 0.720 AC: 7623 AN: 10594

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.645 AC: 43863 AN: 67986

Other (OTH) AF: 0.689 AC: 1450 AN: 2106

Alfa AF: 0.655 Hom.: 161359

Bravo AF: 0.675

TwinsUK AF: 0.652 AC: 2419

ALSPAC AF: 0.641 AC: 2469

ESP6500AA AF: 0.780 AC: 3437

ESP6500EA AF: 0.654 AC: 5621

ExAC AF: 0.638 AC: 77488

Asia WGS AF: 0.557 AC: 1940 AN: 3478

EpiCase AF: 0.657

EpiControl AF: 0.661

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 04, 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

- -

Jan 05, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 80% 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: 74. Only high quality variants are reported. -

Bethlem myopathy 1A Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dystonia 27 Benign:1

Jul 30, 2021

Genome-Nilou Lab

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Ullrich congenital muscular dystrophy 1A Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.7
DANN	Benign	0.28
DEOGEN2	Benign	0.13	.;T;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.034	T;T;T;T;.
MetaRNN	Benign	0.0000013	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.9	.;N;.;.;.
PhyloP100		1.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.0	N;N;N;.;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;T;.;T
Sift4G	Benign	0.66	T;T;T;T;T
Polyphen		0.0	B;B;.;.;B
Vest4		0.0090
MPC		0.17
ClinPred		0.00058	T
GERP RS		2.2
Varity_R		0.037
gMVP		0.058
Mutation Taster		=100/0	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: rs6728818; hg19: chr2-238244963; COSMIC: COSV55081834; COSMIC: COSV55081834;