rs200285455

Positions:

• chr2-237365884-G-A
• chr2-237365884-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_004369.4(COL6A3):​c.5652C>T​(p.Thr1884Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -6.71

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 2-237365884-G-A is Benign according to our data. Variant chr2-237365884-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286041.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=-6.71 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.5652C>T	p.Thr1884Thr	synonymous_variant	12/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.5034C>T	p.Thr1678Thr	synonymous_variant	11/43		NP_476508.2
COL6A3	NM_057166.5	c.3831C>T	p.Thr1277Thr	synonymous_variant	9/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.5652C>T	p.Thr1884Thr	synonymous_variant	12/44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.3831C>T	p.Thr1277Thr	synonymous_variant	9/41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.5034C>T	p.Thr1678Thr	synonymous_variant	11/43	5		ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000350 AC: 88 AN: 251288 Hom.: 0 AF XY: 0.000368 AC XY: 50 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000206 AC: 301 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.000220 AC XY: 160 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74476

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000178

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	COL6A3: BP4, BP7 -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.011
DANN	Benign	0.35

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: rs200285455; hg19: chr2-238274527;