rs2646264

Variant names:

• chr2-237348570-C-G
• rs2646264
• NM_004369.4:c.6930+43G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-237348570-C-G
• chr2-237348570-C-T

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.6930+43G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,593,010 control chromosomes in the GnomAD database, including 9,430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (934 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8496 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.520
• 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=-0.81).
• BP6: Variant 2-237348570-C-G is Benign according to our data. Variant chr2-237348570-C-G is described in ClinVar as Benign. ClinVar VariationId is 94974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6930+43G>C		intron_variant	Intron 29 of 43	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.6312+43G>C		intron_variant	Intron 28 of 42		NP_476508.2
COL6A3	NM_057166.5	c.5109+43G>C		intron_variant	Intron 26 of 40		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6930+43G>C		intron_variant	Intron 29 of 43	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.5109+43G>C		intron_variant	Intron 26 of 40	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.6312+43G>C		intron_variant	Intron 28 of 42	5		ENSP00000315873.4
COL6A3	ENST00000491769.1	n.1184+43G>C		intron_variant	Intron 6 of 19	5

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16475 AN: 152148 Hom.: 934 Cov.: 32

Gnomad AFR AF: 0.0951

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0489

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.115 AC: 27945 AN: 243366 AF XY: 0.114

Gnomad AFR exome AF: 0.0946

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.0471

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.107 AC: 153857 AN: 1440744 Hom.: 8496 Cov.: 29 AF XY: 0.107 AC XY: 76852 AN XY: 717192

African (AFR) AF: 0.0960 AC: 3175 AN: 33062

American (AMR) AF: 0.172 AC: 7593 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3222 AN: 25958

East Asian (EAS) AF: 0.0523 AC: 2063 AN: 39476

South Asian (SAS) AF: 0.119 AC: 10148 AN: 84942

European-Finnish (FIN) AF: 0.113 AC: 6010 AN: 53146

Middle Eastern (MID) AF: 0.145 AC: 835 AN: 5746

European-Non Finnish (NFE) AF: 0.105 AC: 114529 AN: 1094624

Other (OTH) AF: 0.105 AC: 6282 AN: 59634

GnomAD4 genome AF: 0.108 AC: 16482 AN: 152266 Hom.: 934 Cov.: 32 AF XY: 0.111 AC XY: 8253 AN XY: 74446

African (AFR) AF: 0.0950 AC: 3945 AN: 41540

American (AMR) AF: 0.164 AC: 2504 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 463 AN: 3464

East Asian (EAS) AF: 0.0488 AC: 253 AN: 5184

South Asian (SAS) AF: 0.118 AC: 569 AN: 4826

European-Finnish (FIN) AF: 0.114 AC: 1206 AN: 10610

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7159 AN: 68022

Other (OTH) AF: 0.119 AC: 251 AN: 2116

Alfa AF: 0.0631 Hom.: 94

Bravo AF: 0.110

Asia WGS AF: 0.0800 AC: 281 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 38% 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: 35. Only high quality variants are reported. -

Nov 05, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.69
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs2646264; hg19: chr2-238257213; COSMIC: COSV107337570;