2-237340465-T-C

Variant names:

• chr2-237340465-T-C
• rs61729844
• NM_004369.4:c.8451A>G
• COL6A3 p.Pro2817Pro

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.8451A>G​(p.Pro2817Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0945 in 1,612,866 control chromosomes in the GnomAD database, including 8,121 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. P2817P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.069 (472 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7649 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -6.63
• Publications: 10 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
• Ullrich congenital muscular dystrophy 1C

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• collagen 6-related myopathy

  Inheritance: SD, AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• dystonia 27

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

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-1.02).
• BP6: Variant 2-237340465-T-C is Benign according to our data. Variant chr2-237340465-T-C is described in ClinVar as Benign. ClinVar VariationId is 95003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 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.8451A>G	p.Pro2817Pro	synonymous	Exon 38 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.7833A>G	p.Pro2611Pro	synonymous	Exon 37 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.6630A>G	p.Pro2210Pro	synonymous	Exon 35 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.8451A>G	p.Pro2817Pro	synonymous	Exon 38 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.6630A>G	p.Pro2210Pro	synonymous	Exon 35 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.7833A>G	p.Pro2611Pro	synonymous	Exon 37 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10451 AN: 152150 Hom.: 472 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0489

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.00945

Gnomad SAS AF: 0.0636

Gnomad FIN AF: 0.0914

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0641

GnomAD2 exomes AF: 0.0745 AC: 18646 AN: 250156 AF XY: 0.0770

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.0391

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0101

Gnomad FIN exome AF: 0.0934

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0743

GnomAD4 exome AF: 0.0972 AC: 141954 AN: 1460598 Hom.: 7649 Cov.: 32 AF XY: 0.0963 AC XY: 69948 AN XY: 726676

African (AFR) AF: 0.0158 AC: 528 AN: 33476

American (AMR) AF: 0.0413 AC: 1848 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2908 AN: 26134

East Asian (EAS) AF: 0.00967 AC: 384 AN: 39698

South Asian (SAS) AF: 0.0650 AC: 5604 AN: 86238

European-Finnish (FIN) AF: 0.0925 AC: 4851 AN: 52442

Middle Eastern (MID) AF: 0.0462 AC: 262 AN: 5674

European-Non Finnish (NFE) AF: 0.108 AC: 120201 AN: 1111854

Other (OTH) AF: 0.0889 AC: 5368 AN: 60362

GnomAD4 genome AF: 0.0686 AC: 10445 AN: 152268 Hom.: 472 Cov.: 32 AF XY: 0.0669 AC XY: 4978 AN XY: 74452

African (AFR) AF: 0.0188 AC: 782 AN: 41568

American (AMR) AF: 0.0488 AC: 747 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3472

East Asian (EAS) AF: 0.00947 AC: 49 AN: 5174

South Asian (SAS) AF: 0.0634 AC: 305 AN: 4810

European-Finnish (FIN) AF: 0.0914 AC: 969 AN: 10606

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6956 AN: 68016

Other (OTH) AF: 0.0629 AC: 133 AN: 2114

Alfa AF: 0.0855 Hom.: 433

Bravo AF: 0.0647

Asia WGS AF: 0.0430 AC: 151 AN: 3478

EpiCase AF: 0.101

EpiControl AF: 0.0999

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0020
DANN	Benign	0.41
PhyloP100		-6.6
Mutation Taster		=84/16	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61729844;

hg19: chr2-238249108;

COSMIC: COSV55108426;