chr2-237359074-C-T

Variant names:

• chr2-237359074-C-T
• rs2646254
• NM_004369.4:c.6369G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.6369G>A​(p.Leu2123Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,612,952 control chromosomes in the GnomAD database, including 30,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2123L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.25 (6552 hom., cov: 33)
  • Exomes 𝑓: 0.16 (23936 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0350
• Publications: 20 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, SD, AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

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

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, SD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, ClinGen, Orphanet
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-237359074-C-T is Benign according to our data. Variant chr2-237359074-C-T is described in ClinVar as Benign. ClinVar VariationId is 94962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	NM_004369.4	MANE Select	c.6369G>A	p.Leu2123Leu	synonymous	Exon 20 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.5751G>A	p.Leu1917Leu	synonymous	Exon 19 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.4548G>A	p.Leu1516Leu	synonymous	Exon 17 of 41	NP_476507.3	P12111-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.6369G>A	p.Leu2123Leu	synonymous	Exon 20 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.4548G>A	p.Leu1516Leu	synonymous	Exon 17 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.5751G>A	p.Leu1917Leu	synonymous	Exon 19 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38527 AN: 152028 Hom.: 6518 Cov.: 33

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.213 AC: 53684 AN: 251486 AF XY: 0.206

Gnomad AFR exome AF: 0.487

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.360

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.165 AC: 240631 AN: 1460806 Hom.: 23936 Cov.: 35 AF XY: 0.166 AC XY: 120329 AN XY: 726750

African (AFR) AF: 0.489 AC: 16339 AN: 33428

American (AMR) AF: 0.288 AC: 12882 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4264 AN: 26132

East Asian (EAS) AF: 0.335 AC: 13307 AN: 39688

South Asian (SAS) AF: 0.251 AC: 21637 AN: 86218

European-Finnish (FIN) AF: 0.124 AC: 6626 AN: 53420

Middle Eastern (MID) AF: 0.225 AC: 1294 AN: 5762

European-Non Finnish (NFE) AF: 0.138 AC: 152977 AN: 1111080

Other (OTH) AF: 0.187 AC: 11305 AN: 60356

GnomAD4 genome AF: 0.254 AC: 38623 AN: 152146 Hom.: 6552 Cov.: 33 AF XY: 0.256 AC XY: 19024 AN XY: 74396

African (AFR) AF: 0.468 AC: 19423 AN: 41472

American (AMR) AF: 0.278 AC: 4247 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 598 AN: 3472

East Asian (EAS) AF: 0.355 AC: 1838 AN: 5174

South Asian (SAS) AF: 0.262 AC: 1262 AN: 4812

European-Finnish (FIN) AF: 0.121 AC: 1280 AN: 10610

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9250 AN: 68006

Other (OTH) AF: 0.248 AC: 524 AN: 2110

Alfa AF: 0.182 Hom.: 10730

Bravo AF: 0.273

Asia WGS AF: 0.306 AC: 1067 AN: 3478

EpiCase AF: 0.143

EpiControl AF: 0.140

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Dystonia 27 (1)
-	-	1	not provided (1)
-	-	1	Ullrich congenital muscular dystrophy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	8.5
DANN	Benign	0.74
PhyloP100		-0.035
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs2646254; hg19: chr2-238267717; COSMIC: COSV55083693; COSMIC: COSV55083693;