2-237346477-C-T

Variant names:

• chr2-237346477-C-T
• rs2270656
• NM_004369.4:c.7092+26G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000295550.9(COL6A3):​c.7092+26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,606,726 control chromosomes in the GnomAD database, including 17,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3481 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13709 hom.)
• Consequence: COL6A3 ENST00000295550.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0190
• Publications: 8 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=-0.89).
• BP6: Variant 2-237346477-C-T is Benign according to our data. Variant chr2-237346477-C-T is described in ClinVar as Benign. ClinVar VariationId is 94979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000295550.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	NM_004369.4	MANE Select	c.7092+26G>A		intron	N/A	NP_004360.2
	COL6A3	NM_057167.4		c.6474+26G>A		intron	N/A	NP_476508.2
	COL6A3	NM_057166.5		c.5271+26G>A		intron	N/A	NP_476507.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.7092+26G>A		intron	N/A	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.5271+26G>A		intron	N/A	ENSP00000418285.1
	COL6A3	ENST00000353578.9	TSL:5	c.6474+26G>A		intron	N/A	ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28625 AN: 151922 Hom.: 3475 Cov.: 32

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.0526

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.193

GnomAD2 exomes AF: 0.150 AC: 37751 AN: 251186 AF XY: 0.146

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.0512

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.130 AC: 188405 AN: 1454686 Hom.: 13709 Cov.: 30 AF XY: 0.129 AC XY: 93627 AN XY: 724072

African (AFR) AF: 0.345 AC: 11492 AN: 33272

American (AMR) AF: 0.204 AC: 9099 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 4263 AN: 26036

East Asian (EAS) AF: 0.0536 AC: 2127 AN: 39646

South Asian (SAS) AF: 0.145 AC: 12516 AN: 86050

European-Finnish (FIN) AF: 0.118 AC: 6314 AN: 53348

Middle Eastern (MID) AF: 0.217 AC: 1183 AN: 5440

European-Non Finnish (NFE) AF: 0.120 AC: 132923 AN: 1106122

Other (OTH) AF: 0.141 AC: 8488 AN: 60092

GnomAD4 genome AF: 0.189 AC: 28664 AN: 152040 Hom.: 3481 Cov.: 32 AF XY: 0.188 AC XY: 13958 AN XY: 74330

African (AFR) AF: 0.334 AC: 13841 AN: 41416

American (AMR) AF: 0.207 AC: 3168 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 595 AN: 3462

East Asian (EAS) AF: 0.0524 AC: 271 AN: 5174

South Asian (SAS) AF: 0.141 AC: 678 AN: 4812

European-Finnish (FIN) AF: 0.119 AC: 1255 AN: 10584

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8305 AN: 67994

Other (OTH) AF: 0.191 AC: 402 AN: 2110

Alfa AF: 0.162 Hom.: 550

Bravo AF: 0.201

Asia WGS AF: 0.112 AC: 392 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Dystonia 27 (1)
-	-	1	Ullrich congenital muscular dystrophy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.4
DANN	Benign	0.46
PhyloP100		0.019
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: rs2270656; hg19: chr2-238255120;