2-237340458-C-T

Variant names:

• chr2-237340458-C-T
• rs115171119
• NM_004369.4:c.8458G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004369.4(COL6A3):​c.8458G>A​(p.Val2820Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,612,446 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V2820V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.11
• Publications: 3 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 (MetaRNN=0.0075490475).
• BP6: Variant 2-237340458-C-T is Benign according to our data. Variant chr2-237340458-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 283682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00251 (382/152314) while in subpopulation AFR AF = 0.0084 (349/41572). AF 95% confidence interval is 0.00767. There are 2 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,SD gene

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.8458G>A	p.Val2820Ile	missense	Exon 38 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.7840G>A	p.Val2614Ile	missense	Exon 37 of 43	NP_476508.2
	COL6A3	NM_057166.5		c.6637G>A	p.Val2213Ile	missense	Exon 35 of 41	NP_476507.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.8458G>A	p.Val2820Ile	missense	Exon 38 of 44	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.6637G>A	p.Val2213Ile	missense	Exon 35 of 41	ENSP00000418285.1
	COL6A3	ENST00000353578.9	TSL:5	c.7840G>A	p.Val2614Ile	missense	Exon 37 of 43	ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 379 AN: 152196 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00835

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.000689 AC: 172 AN: 249604 AF XY: 0.000577

Gnomad AFR exome AF: 0.00914

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000260 AC: 379 AN: 1460132 Hom.: 2 Cov.: 31 AF XY: 0.000248 AC XY: 180 AN XY: 726498

African (AFR) AF: 0.00747 AC: 250 AN: 33468

American (AMR) AF: 0.000581 AC: 26 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51972

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5624

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111916

Other (OTH) AF: 0.000762 AC: 46 AN: 60356

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152314 Hom.: 2 Cov.: 33 AF XY: 0.00243 AC XY: 181 AN XY: 74472

African (AFR) AF: 0.00840 AC: 349 AN: 41572

American (AMR) AF: 0.00105 AC: 16 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00103 Hom.: 2

Bravo AF: 0.00289

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000865 AC: 105

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.0
DANN	Benign	0.91
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.1
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.095
Sift	Benign	0.54	T
Sift4G	Benign	0.72	T
Polyphen		0.0010	B
Vest4		0.11
MVP		0.73
MPC		0.12
ClinPred		0.0025	T
GERP RS		1.5
Varity_R		0.022
gMVP		0.25
Mutation Taster		=99/1	polymorphism

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: rs115171119; hg19: chr2-238249101; COSMIC: COSV99040651;