2-237339091-C-G

Variant names:

• chr2-237339091-C-G
• rs36104025
• NM_004369.4:c.8491G>C

Variant summary

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

The NM_004369.4(COL6A3):​c.8491G>C​(p.Asp2831His) variant causes a missense change. The variant allele was found at a frequency of 0.0831 in 1,612,822 control chromosomes in the GnomAD database, including 6,300 homozygotes. In-silico tool predicts 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. D2831Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.059 (369 hom., cov: 33)
  • Exomes 𝑓: 0.086 (5931 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.46
• Publications: 15 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=0.0027243495).
• BP6: Variant 2-237339091-C-G is Benign according to our data. Variant chr2-237339091-C-G is described in ClinVar as Benign. ClinVar VariationId is 95006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.088 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.8491G>C	p.Asp2831His	missense	Exon 39 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.7873G>C	p.Asp2625His	missense	Exon 38 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.6670G>C	p.Asp2224His	missense	Exon 36 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.8491G>C	p.Asp2831His	missense	Exon 39 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.6670G>C	p.Asp2224His	missense	Exon 36 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.7873G>C	p.Asp2625His	missense	Exon 38 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8959 AN: 152024 Hom.: 367 Cov.: 33

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0700

Gnomad FIN AF: 0.0583

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0899

Gnomad OTH AF: 0.0523

GnomAD2 exomes AF: 0.0655 AC: 16463 AN: 251286 AF XY: 0.0689

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.0322

Gnomad ASJ exome AF: 0.0971

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0594

Gnomad NFE exome AF: 0.0894

Gnomad OTH exome AF: 0.0737

GnomAD4 exome AF: 0.0856 AC: 125027 AN: 1460680 Hom.: 5931 Cov.: 30 AF XY: 0.0857 AC XY: 62301 AN XY: 726710

African (AFR) AF: 0.0127 AC: 424 AN: 33478

American (AMR) AF: 0.0339 AC: 1516 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0912 AC: 2383 AN: 26128

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39692

South Asian (SAS) AF: 0.0754 AC: 6500 AN: 86212

European-Finnish (FIN) AF: 0.0622 AC: 3323 AN: 53400

Middle Eastern (MID) AF: 0.0928 AC: 535 AN: 5764

European-Non Finnish (NFE) AF: 0.0944 AC: 104915 AN: 1110926

Other (OTH) AF: 0.0898 AC: 5419 AN: 60370

GnomAD4 genome AF: 0.0589 AC: 8961 AN: 152142 Hom.: 369 Cov.: 33 AF XY: 0.0551 AC XY: 4095 AN XY: 74358

African (AFR) AF: 0.0172 AC: 716 AN: 41510

American (AMR) AF: 0.0453 AC: 692 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0931 AC: 323 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0709 AC: 341 AN: 4810

European-Finnish (FIN) AF: 0.0583 AC: 617 AN: 10588

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0899 AC: 6112 AN: 67982

Other (OTH) AF: 0.0508 AC: 107 AN: 2108

Alfa AF: 0.0787 Hom.: 437

Bravo AF: 0.0575

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.0992 AC: 853

ExAC AF: 0.0671 AC: 8147

Asia WGS AF: 0.0290 AC: 103 AN: 3478

EpiCase AF: 0.0963

EpiControl AF: 0.0930

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.5
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.30
MPC		0.18
ClinPred		0.038	T
GERP RS		5.1
Varity_R		0.31
gMVP		0.51
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs36104025; hg19: chr2-238247734;