chr2-237348370-G-A

Variant names:

• chr2-237348370-G-A
• rs2646265
• NM_004369.4:c.6945C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004369.4(COL6A3):​c.6945C>T​(p.Phe2315Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,603,108 control chromosomes in the GnomAD database, including 9,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (917 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8392 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.965
• Publications: 17 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: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AR, SD, AD 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, Illumina
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 2-237348370-G-A is Benign according to our data. Variant chr2-237348370-G-A is described in ClinVar as Benign. ClinVar VariationId is 94975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.965 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.157 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.6945C>T	p.Phe2315Phe	synonymous	Exon 30 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.6327C>T	p.Phe2109Phe	synonymous	Exon 29 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.5124C>T	p.Phe1708Phe	synonymous	Exon 27 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.6945C>T	p.Phe2315Phe	synonymous	Exon 30 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.5124C>T	p.Phe1708Phe	synonymous	Exon 27 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.6327C>T	p.Phe2109Phe	synonymous	Exon 29 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16247 AN: 152080 Hom.: 917 Cov.: 32

Gnomad AFR AF: 0.0899

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0487

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: 0.114 AC: 28654 AN: 250870 AF XY: 0.114

Gnomad AFR exome AF: 0.0883

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.0470

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.105 AC: 151968 AN: 1450910 Hom.: 8392 Cov.: 30 AF XY: 0.105 AC XY: 76127 AN XY: 722574

African (AFR) AF: 0.0894 AC: 2976 AN: 33282

American (AMR) AF: 0.171 AC: 7641 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 3203 AN: 26048

East Asian (EAS) AF: 0.0518 AC: 2056 AN: 39654

South Asian (SAS) AF: 0.119 AC: 10221 AN: 86004

European-Finnish (FIN) AF: 0.113 AC: 6037 AN: 53398

Middle Eastern (MID) AF: 0.145 AC: 830 AN: 5742

European-Non Finnish (NFE) AF: 0.102 AC: 112824 AN: 1102066

Other (OTH) AF: 0.103 AC: 6180 AN: 60024

GnomAD4 genome AF: 0.107 AC: 16254 AN: 152198 Hom.: 917 Cov.: 32 AF XY: 0.109 AC XY: 8143 AN XY: 74402

African (AFR) AF: 0.0898 AC: 3728 AN: 41524

American (AMR) AF: 0.163 AC: 2488 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 464 AN: 3464

East Asian (EAS) AF: 0.0487 AC: 252 AN: 5178

South Asian (SAS) AF: 0.118 AC: 568 AN: 4820

European-Finnish (FIN) AF: 0.114 AC: 1204 AN: 10592

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

European-Non Finnish (NFE) AF: 0.105 AC: 7168 AN: 68014

Other (OTH) AF: 0.118 AC: 250 AN: 2114

Alfa AF: 0.108 Hom.: 3031

Bravo AF: 0.108

Asia WGS AF: 0.0800 AC: 280 AN: 3478

EpiCase AF: 0.114

EpiControl AF: 0.110

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.6
DANN	Benign	0.72
PhyloP100		0.96
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: rs2646265; hg19: chr2-238257013; COSMIC: COSV107337569;