chr2-237395263-A-G

Variant names:

• chr2-237395263-A-G
• rs2645778
• NM_004369.4:c.92-59T>C

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.92-59T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,582,598 control chromosomes in the GnomAD database, including 66,551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11199 hom., cov: 33)
  • Exomes 𝑓: 0.27 (55352 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0420

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=-0.83).
• BP6: Variant 2-237395263-A-G is Benign according to our data. Variant chr2-237395263-A-G is described in ClinVar as [Benign]. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.92-59T>C		intron_variant	Intron 2 of 43	ENST00000295550.9	NP_004360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.92-59T>C		intron_variant	Intron 2 of 43	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54198 AN: 152022 Hom.: 11163 Cov.: 33

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.336

GnomAD4 exome AF: 0.271 AC: 388321 AN: 1430458 Hom.: 55352 AF XY: 0.270 AC XY: 192203 AN XY: 711620

Gnomad4 AFR exome AF: 0.584

Gnomad4 AMR exome AF: 0.373

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.313

Gnomad4 SAS exome AF: 0.282

Gnomad4 FIN exome AF: 0.278

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.357 AC: 54294 AN: 152140 Hom.: 11199 Cov.: 33 AF XY: 0.359 AC XY: 26721 AN XY: 74390

Gnomad4 AFR AF: 0.575

Gnomad4 AMR AF: 0.351

Gnomad4 ASJ AF: 0.245

Gnomad4 EAS AF: 0.331

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.338

Alfa AF: 0.317 Hom.: 1780

Bravo AF: 0.371

Asia WGS AF: 0.344 AC: 1199 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 56% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 52. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.0
DANN	Benign	0.87

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: rs2645778; hg19: chr2-238303906; COSMIC: COSV55094933;