rs75780727

Variant names:

• chr2-237371723-C-T
• rs75780727
• ENST00000392004.7:c.3676G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_057165.5(COL6A3):​c.3676G>A​(p.Gly1226Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,581,268 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (234 hom.)
• Consequence: COL6A3 NM_057165.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.164
• Publications: 5 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=0.0021382868).
• BP6: Variant 2-237371723-C-T is Benign according to our data. Variant chr2-237371723-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0533 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_057165.5. 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.4285+9G>A		intron	N/A	NP_004360.2	D9ZGF2
	COL6A3	NM_057165.5		c.3676G>A	p.Gly1226Arg	missense	Exon 8 of 8	NP_476506.3	P12111-5
	COL6A3	NM_057164.5		c.3073G>A	p.Gly1025Arg	missense	Exon 7 of 7	NP_476505.3	P12111-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000392004.7	TSL:1	c.3676G>A	p.Gly1226Arg	missense	Exon 8 of 8	ENSP00000375861.3	P12111-5
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.4285+9G>A		intron	N/A	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.2464+9G>A		intron	N/A	ENSP00000418285.1	P12111-4

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 945 AN: 152176 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0561

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.0139 AC: 3238 AN: 233252 AF XY: 0.0104

Gnomad AFR exome AF: 0.000943

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00319

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000653

Gnomad OTH exome AF: 0.00989

GnomAD4 exome AF: 0.00301 AC: 4307 AN: 1428974 Hom.: 234 Cov.: 31 AF XY: 0.00253 AC XY: 1789 AN XY: 706876

African (AFR) AF: 0.00137 AC: 44 AN: 32080

American (AMR) AF: 0.0954 AC: 3830 AN: 40126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24414

East Asian (EAS) AF: 0.00597 AC: 234 AN: 39198

South Asian (SAS) AF: 0.000144 AC: 12 AN: 83212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.0000274 AC: 30 AN: 1093184

Other (OTH) AF: 0.00268 AC: 157 AN: 58646

GnomAD4 genome AF: 0.00624 AC: 951 AN: 152294 Hom.: 44 Cov.: 32 AF XY: 0.00720 AC XY: 536 AN XY: 74468

African (AFR) AF: 0.00115 AC: 48 AN: 41562

American (AMR) AF: 0.0564 AC: 863 AN: 15304

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

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00223 Hom.: 25

Bravo AF: 0.0108

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0104 AC: 1258

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	COL6A3-related disorder (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.5
DANN	Benign	0.62
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.16
PROVEAN	Benign	0.67	N
REVEL	Benign	0.050
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.048	D
Vest4		0.099
MutPred		0.51		Gain of sheet (P = 0.0149)
ClinPred		0.0024	T
GERP RS		-1.2
PromoterAI		-0.015	Neutral
Mutation Taster		=99/1	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: rs75780727; hg19: chr2-238280366; COSMIC: COSV55116473;