rs72986111

Positions:

• chr2-237348585-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000295550.9(COL6A3):​c.6930+28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,609,298 control chromosomes in the GnomAD database, including 1,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (85 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1030 hom.)
• Consequence: COL6A3 ENST00000295550.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.86

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=-0.87).
• BP6: Variant 2-237348585-G-A is Benign according to our data. Variant chr2-237348585-G-A is described in ClinVar as [Benign]. Clinvar id is 94973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237348585-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0265 (4039/152246) while in subpopulation SAS AF= 0.0392 (189/4820). AF 95% confidence interval is 0.0348. There are 85 homozygotes in gnomad4. There are 2054 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 85 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6930+28C>T		intron_variant		ENST00000295550.9	NP_004360.2
COL6A3	NM_057166.5	c.5109+28C>T		intron_variant			NP_476507.3
COL6A3	NM_057167.4	c.6312+28C>T		intron_variant			NP_476508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6930+28C>T		intron_variant		1	NM_004369.4	ENSP00000295550	P1
COL6A3	ENST00000472056.5	c.5109+28C>T		intron_variant		1		ENSP00000418285
COL6A3	ENST00000353578.9	c.6312+28C>T		intron_variant		5		ENSP00000315873
COL6A3	ENST00000491769.1	n.1184+28C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4041 AN: 152128 Hom.: 85 Cov.: 33

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.0551

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.0392

Gnomad FIN AF: 0.0623

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0360

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0308 AC: 7676 AN: 249268 Hom.: 161 AF XY: 0.0326 AC XY: 4384 AN XY: 134662

Gnomad AFR exome AF: 0.00595

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0265

Gnomad EAS exome AF: 0.0115

Gnomad SAS exome AF: 0.0401

Gnomad FIN exome AF: 0.0563

Gnomad NFE exome AF: 0.0364

Gnomad OTH exome AF: 0.0271

GnomAD4 exome AF: 0.0349 AC: 50898 AN: 1457052 Hom.: 1030 Cov.: 31 AF XY: 0.0351 AC XY: 25478 AN XY: 724930

Gnomad4 AFR exome AF: 0.00446

Gnomad4 AMR exome AF: 0.0129

Gnomad4 ASJ exome AF: 0.0274

Gnomad4 EAS exome AF: 0.0103

Gnomad4 SAS exome AF: 0.0395

Gnomad4 FIN exome AF: 0.0569

Gnomad4 NFE exome AF: 0.0366

Gnomad4 OTH exome AF: 0.0327

GnomAD4 genome AF: 0.0265 AC: 4039 AN: 152246 Hom.: 85 Cov.: 33 AF XY: 0.0276 AC XY: 2054 AN XY: 74422

Gnomad4 AFR AF: 0.00635

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.0392

Gnomad4 FIN AF: 0.0623

Gnomad4 NFE AF: 0.0360

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0331 Hom.: 34

Bravo AF: 0.0228

Asia WGS AF: 0.0370 AC: 130 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
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	-0.87
CADD	Benign	0.17
DANN	Benign	0.69

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: rs72986111; hg19: chr2-238257228; COSMIC: COSV55108482;