rs61729839

Variant names:

• chr2-237368736-C-T
• rs61729839
• NM_004369.4:c.4727G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-237368736-C-T
• chr2-237368736-C-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.4727G>A​(p.Arg1576Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,614,182 control chromosomes in the GnomAD database, including 244 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1576W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (18 hom., cov: 32)
  • Exomes 𝑓: 0.016 (226 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.15
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046691597).
• BP6: Variant 2-237368736-C-T is Benign according to our data. Variant chr2-237368736-C-T is described in ClinVar as Benign. ClinVar VariationId is 94938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0105 (1593/152288) while in subpopulation NFE AF = 0.0172 (1171/68012). AF 95% confidence interval is 0.0164. There are 18 homozygotes in GnomAd4. There are 757 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.4727G>A	p.Arg1576Gln	missense	Exon 10 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.4109G>A	p.Arg1370Gln	missense	Exon 9 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.2906G>A	p.Arg969Gln	missense	Exon 7 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.4727G>A	p.Arg1576Gln	missense	Exon 10 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.2906G>A	p.Arg969Gln	missense	Exon 7 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.4109G>A	p.Arg1370Gln	missense	Exon 9 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1594 AN: 152170 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00994 AC: 2501 AN: 251486 AF XY: 0.0103

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00568

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.0159 AC: 23304 AN: 1461894 Hom.: 226 Cov.: 34 AF XY: 0.0156 AC XY: 11324 AN XY: 727248

African (AFR) AF: 0.00245 AC: 82 AN: 33480

American (AMR) AF: 0.00537 AC: 240 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00552 AC: 476 AN: 86258

European-Finnish (FIN) AF: 0.00569 AC: 304 AN: 53420

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.0192 AC: 21398 AN: 1112012

Other (OTH) AF: 0.0120 AC: 727 AN: 60396

GnomAD4 genome AF: 0.0105 AC: 1593 AN: 152288 Hom.: 18 Cov.: 32 AF XY: 0.0102 AC XY: 757 AN XY: 74472

African (AFR) AF: 0.00298 AC: 124 AN: 41558

American (AMR) AF: 0.0119 AC: 182 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4824

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1171 AN: 68012

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.0147 Hom.: 34

Bravo AF: 0.0106

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0210 AC: 81

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0156 AC: 134

ExAC AF: 0.0103 AC: 1246

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0154

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.28
Sift	Benign	0.073	T
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.23
MPC		0.38
ClinPred		0.014	T
GERP RS		4.5
Varity_R		0.21
gMVP		0.72
Mutation Taster		=96/4	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: rs61729839; hg19: chr2-238277379; COSMIC: COSV99799739; COSMIC: COSV99799739;