rs151079701

Variant names:

• chr2-237344373-G-A
• rs151079701
• NM_004369.4:c.7645C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237344373-G-A
• chr2-237344373-G-T

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.7645C>T​(p.Arg2549Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000986 in 1,614,164 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2549Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (16 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.919
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074534714).
• BP6: Variant 2-237344373-G-A is Benign according to our data. Variant chr2-237344373-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00211 (322/152288) while in subpopulation AMR AF = 0.0191 (292/15298). AF 95% confidence interval is 0.0173. There are 4 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.7645C>T	p.Arg2549Trp	missense	Exon 36 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.7027C>T	p.Arg2343Trp	missense	Exon 35 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.5824C>T	p.Arg1942Trp	missense	Exon 33 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.7645C>T	p.Arg2549Trp	missense	Exon 36 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.5824C>T	p.Arg1942Trp	missense	Exon 33 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.7027C>T	p.Arg2343Trp	missense	Exon 35 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 152170 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00378 AC: 950 AN: 251268 AF XY: 0.00279

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.000868 AC: 1269 AN: 1461876 Hom.: 16 Cov.: 31 AF XY: 0.000727 AC XY: 529 AN XY: 727238

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.0256 AC: 1144 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1112008

Other (OTH) AF: 0.00103 AC: 62 AN: 60396

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152288 Hom.: 4 Cov.: 32 AF XY: 0.00252 AC XY: 188 AN XY: 74464

African (AFR) AF: 0.000577 AC: 24 AN: 41564

American (AMR) AF: 0.0191 AC: 292 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000649 Hom.: 2

Bravo AF: 0.00322

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00266 AC: 323

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	COL6A3-related disorder (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Ullrich congenital muscular dystrophy 1A;C4225336:Dystonia 27;CN029274:Bethlem myopathy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0075	T
MetaSVM	Uncertain	0.0030	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.92
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.94
MPC		0.15
ClinPred		0.032	T
GERP RS		3.1
PromoterAI		-0.0081	Neutral
Varity_R		0.11
gMVP		0.56
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs151079701; hg19: chr2-238253016; COSMIC: COSV55093410; COSMIC: COSV55093410;