rs78071799

chr2-237350114-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.6879+33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,608,338 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (180 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0600

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=-0.88).
• BP6: Variant 2-237350114-G-A is Benign according to our data. Variant chr2-237350114-G-A is described in ClinVar as [Benign]. Clinvar id is 259314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.095 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.6879+33C>T		intron_variant		ENST00000295550.9
COL6A3	NM_057166.5	c.5058+33C>T		intron_variant
COL6A3	NM_057167.4	c.6261+33C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.6879+33C>T		intron_variant		1	NM_004369.4	P1
COL6A3	ENST00000472056.5	c.5058+33C>T		intron_variant		1
COL6A3	ENST00000353578.9	c.6261+33C>T		intron_variant		5
COL6A3	ENST00000491769.1	n.1133+33C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 579 AN: 152104 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00852 AC: 2140 AN: 251190 Hom.: 101 AF XY: 0.00804 AC XY: 1092 AN XY: 135780

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.110

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00301 AC: 4379 AN: 1456114 Hom.: 180 Cov.: 29 AF XY: 0.00299 AC XY: 2169 AN XY: 724682

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.0944

Gnomad4 SAS exome AF: 0.00229

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000352

Gnomad4 OTH exome AF: 0.00586

GnomAD4 genome AF: 0.00378 AC: 575 AN: 152224 Hom.: 33 Cov.: 33 AF XY: 0.00431 AC XY: 321 AN XY: 74426

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.102

Gnomad4 SAS AF: 0.00437

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00110 Hom.: 1

Bravo AF: 0.00465

Asia WGS AF: 0.0390 AC: 135 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2018

- -

COL6A3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.86
Dann	Benign	0.65

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: rs78071799; hg19: chr2-238258757; COSMIC: COSV55083675;