rs2645778

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1C

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar as Benign. Clinvar id is 1248152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237395263-A-G is described in CliVar 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

African (AFR) AF: 0.584 AC: 19248 AN: 32966

American (AMR) AF: 0.373 AC: 15992 AN: 42850

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5763 AN: 25774

East Asian (EAS) AF: 0.313 AC: 12361 AN: 39448

South Asian (SAS) AF: 0.282 AC: 23636 AN: 83842

European-Finnish (FIN) AF: 0.278 AC: 14277 AN: 51286

Middle Eastern (MID) AF: 0.295 AC: 1446 AN: 4902

European-Non Finnish (NFE) AF: 0.256 AC: 278739 AN: 1090150

Other (OTH) AF: 0.285 AC: 16859 AN: 59240

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

African (AFR) AF: 0.575 AC: 23861 AN: 41484

American (AMR) AF: 0.351 AC: 5373 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 849 AN: 3470

East Asian (EAS) AF: 0.331 AC: 1711 AN: 5176

South Asian (SAS) AF: 0.299 AC: 1444 AN: 4824

European-Finnish (FIN) AF: 0.286 AC: 3025 AN: 10588

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17062 AN: 67994

Other (OTH) AF: 0.338 AC: 712 AN: 2108

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
PhyloP100		-0.042
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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