2-237324111-A-C

Position:

• chr2-237324111-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004369.4(COL6A3):​c.*663T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 151,928 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL6A3 NM_004369.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.26

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-237324111-A-C is Benign according to our data. Variant chr2-237324111-A-C is described in ClinVar as [Benign]. Clinvar id is 335090.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00495 (752/151928) while in subpopulation NFE AF= 0.0057 (387/67924). AF 95% confidence interval is 0.00523. There are 7 homozygotes in gnomad4. There are 355 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.*663T>G		3_prime_UTR_variant	44/44	ENST00000295550.9
COL6A3	NM_057166.5	c.*663T>G		3_prime_UTR_variant	41/41
COL6A3	NM_057167.4	c.*663T>G		3_prime_UTR_variant	43/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.*663T>G		3_prime_UTR_variant	44/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.00493 AC: 749 AN: 151812 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.00361

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.00541

Gnomad FIN AF: 0.000381

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00570

Gnomad OTH AF: 0.00675

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 444 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 270

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00495 AC: 752 AN: 151928 Hom.: 7 Cov.: 32 AF XY: 0.00478 AC XY: 355 AN XY: 74272

Gnomad4 AFR AF: 0.00386

Gnomad4 AMR AF: 0.00361

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00329

Gnomad4 SAS AF: 0.00541

Gnomad4 FIN AF: 0.000381

Gnomad4 NFE AF: 0.00570

Gnomad4 OTH AF: 0.00668

Alfa AF: 0.00448 Hom.: 0

Bravo AF: 0.00567

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.7
DANN	Benign	0.62

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: rs184900191; hg19: chr2-238232754;