chr2-237342196-G-A

Position:

• chr2-237342196-G-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.7669-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.084 in 1,531,106 control chromosomes in the GnomAD database, including 5,950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.066 (395 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5555 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.827

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]

COL6A3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-237342196-G-A is Benign according to our data. Variant chr2-237342196-G-A is described in ClinVar as [Benign]. Clinvar id is 94993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.7669-35C>T		intron_variant		ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.7051-35C>T		intron_variant			NP_476508.2
COL6A3	NM_057166.5	c.5848-35C>T		intron_variant			NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.7669-35C>T		intron_variant		1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes AF: 0.0655 AC: 9965 AN: 152108 Hom.: 392 Cov.: 32

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0481

Gnomad ASJ AF: 0.0933

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0699

Gnomad FIN AF: 0.0581

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0892

Gnomad OTH AF: 0.0565

GnomAD3 exomes AF: 0.0672 AC: 16305 AN: 242500 Hom.: 653 AF XY: 0.0702 AC XY: 9161 AN XY: 130578

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.0331

Gnomad ASJ exome AF: 0.0980

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.0729

Gnomad FIN exome AF: 0.0599

Gnomad NFE exome AF: 0.0894

Gnomad OTH exome AF: 0.0747

GnomAD4 exome AF: 0.0860 AC: 118624 AN: 1378880 Hom.: 5555 Cov.: 22 AF XY: 0.0861 AC XY: 59382 AN XY: 689902

Gnomad4 AFR exome AF: 0.0381

Gnomad4 AMR exome AF: 0.0350

Gnomad4 ASJ exome AF: 0.0918

Gnomad4 EAS exome AF: 0.000280

Gnomad4 SAS exome AF: 0.0753

Gnomad4 FIN exome AF: 0.0622

Gnomad4 NFE exome AF: 0.0945

Gnomad4 OTH exome AF: 0.0915

GnomAD4 genome AF: 0.0656 AC: 9983 AN: 152226 Hom.: 395 Cov.: 32 AF XY: 0.0616 AC XY: 4587 AN XY: 74420

Gnomad4 AFR AF: 0.0416

Gnomad4 AMR AF: 0.0480

Gnomad4 ASJ AF: 0.0933

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0707

Gnomad4 FIN AF: 0.0581

Gnomad4 NFE AF: 0.0893

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0785 Hom.: 97

Bravo AF: 0.0651

Asia WGS AF: 0.0310 AC: 108 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.49
BranchPoint Hunter		1.0

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: rs59232721; hg19: chr2-238250839;