NM_004369.4:c.8735C>T

Variant names:

• chr2-237336365-G-A
• rs112928650
• NM_004369.4:c.8735C>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.8735C>T​(p.Pro2912Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,148 control chromosomes in the GnomAD database, including 78 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (61 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.63

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=0.002975285).
• BP6: Variant 2-237336365-G-A is Benign according to our data. Variant chr2-237336365-G-A is described in ClinVar as [Benign]. Clinvar id is 166936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237336365-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0044 (670/152324) while in subpopulation EAS AF= 0.0328 (170/5188). AF 95% confidence interval is 0.0287. There are 17 homozygotes in gnomad4. There are 465 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.8735C>T	p.Pro2912Leu	missense_variant	Exon 40 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.8117C>T	p.Pro2706Leu	missense_variant	Exon 39 of 43		NP_476508.2
COL6A3	NM_057166.5	c.6914C>T	p.Pro2305Leu	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.8735C>T	p.Pro2912Leu	missense_variant	Exon 40 of 44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 669 AN: 152206 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0325

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00613 AC: 1542 AN: 251362 Hom.: 22 AF XY: 0.00603 AC XY: 820 AN XY: 135890

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0319

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00260 AC: 3801 AN: 1461824 Hom.: 61 Cov.: 34 AF XY: 0.00255 AC XY: 1858 AN XY: 727208

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0317

Gnomad4 SAS exome AF: 0.000846

Gnomad4 FIN exome AF: 0.0319

Gnomad4 NFE exome AF: 0.000498

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.00440 AC: 670 AN: 152324 Hom.: 17 Cov.: 33 AF XY: 0.00624 AC XY: 465 AN XY: 74490

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0328

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0396

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00187 Hom.: 6

Bravo AF: 0.00193

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00589 AC: 714

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 26, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 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. -

Collagen 6-related myopathy Benign:1

Jan 13, 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. -

Bethlem myopathy 1A Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	0.083
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Benign	0.37
DEOGEN2	Benign	0.23	.;T;.;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.87	D;D;D;D;.
MetaRNN	Benign	0.0030	T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.7	.;M;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N;N;N;.;N
REVEL	Benign	0.19
Sift	Benign	0.039	D;T;D;.;D
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		1.0	D;D;.;.;D
Vest4		0.19
MVP		0.86
MPC		0.15
ClinPred		0.023	T
GERP RS		0.76
Varity_R		0.048
gMVP		0.086

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: rs112928650; hg19: chr2-238245008; COSMIC: COSV55102081; COSMIC: COSV55102081;