2-237324109-C-A

Position:

• chr2-237324109-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.*665G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 149,242 control chromosomes in the GnomAD database, including 32,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (31946 hom., cov: 30)
  • Exomes 𝑓: 0.57 (58 hom.)
• Consequence: COL6A3 NM_004369.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02

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 (BayesDel_noAF=-0.82).
• BP6: Variant 2-237324109-C-A is Benign according to our data. Variant chr2-237324109-C-A is described in ClinVar as [Benign]. Clinvar id is 335089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237324109-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.*665G>T		3_prime_UTR_variant	44/44	ENST00000295550.9
COL6A3	NM_057166.5	c.*665G>T		3_prime_UTR_variant	41/41
COL6A3	NM_057167.4	c.*665G>T		3_prime_UTR_variant	43/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.*665G>T		3_prime_UTR_variant	44/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.654 AC: 97230 AN: 148732 Hom.: 31915 Cov.: 30

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.655

GnomAD4 exome AF: 0.574 AC: 240 AN: 418 Hom.: 58 Cov.: 0 AF XY: 0.571 AC XY: 144 AN XY: 252

Gnomad4 FIN exome AF: 0.576

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.654 AC: 97314 AN: 148824 Hom.: 31946 Cov.: 30 AF XY: 0.652 AC XY: 47274 AN XY: 72498

Gnomad4 AFR AF: 0.781

Gnomad4 AMR AF: 0.650

Gnomad4 ASJ AF: 0.608

Gnomad4 EAS AF: 0.553

Gnomad4 SAS AF: 0.675

Gnomad4 FIN AF: 0.588

Gnomad4 NFE AF: 0.596

Gnomad4 OTH AF: 0.656

Alfa AF: 0.473 Hom.: 3652

Bravo AF: 0.657

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.8
DANN	Benign	0.32

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: rs1050785; hg19: chr2-238232752;