rs36117715

Variant names:

• chr2-237353378-G-A
• rs36117715
• NM_004369.4:c.6653C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237353378-G-A
• chr2-237353378-G-T

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.6653C>T​(p.Pro2218Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,613,906 control chromosomes in the GnomAD database, including 2,181 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2218P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.072 (713 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1468 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.355
• Publications: 19 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=0.0039197206).
• BP6: Variant 2-237353378-G-A is Benign according to our data. Variant chr2-237353378-G-A is described in ClinVar as Benign. ClinVar VariationId is 94967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 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.6653C>T	p.Pro2218Leu	missense	Exon 25 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.6035C>T	p.Pro2012Leu	missense	Exon 24 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.4832C>T	p.Pro1611Leu	missense	Exon 22 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.6653C>T	p.Pro2218Leu	missense	Exon 25 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.4832C>T	p.Pro1611Leu	missense	Exon 22 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.6035C>T	p.Pro2012Leu	missense	Exon 24 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10936 AN: 152076 Hom.: 713 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0420

Gnomad ASJ AF: 0.0936

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0328

Gnomad OTH AF: 0.0744

GnomAD2 exomes AF: 0.0418 AC: 10515 AN: 251404 AF XY: 0.0396

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.0297

Gnomad ASJ exome AF: 0.0911

Gnomad EAS exome AF: 0.00457

Gnomad FIN exome AF: 0.00879

Gnomad NFE exome AF: 0.0350

Gnomad OTH exome AF: 0.0446

GnomAD4 exome AF: 0.0348 AC: 50855 AN: 1461712 Hom.: 1468 Cov.: 32 AF XY: 0.0346 AC XY: 25136 AN XY: 727194

African (AFR) AF: 0.182 AC: 6078 AN: 33470

American (AMR) AF: 0.0310 AC: 1388 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0898 AC: 2347 AN: 26132

East Asian (EAS) AF: 0.00353 AC: 140 AN: 39700

South Asian (SAS) AF: 0.0338 AC: 2915 AN: 86252

European-Finnish (FIN) AF: 0.0110 AC: 588 AN: 53388

Middle Eastern (MID) AF: 0.0860 AC: 496 AN: 5768

European-Non Finnish (NFE) AF: 0.0307 AC: 34169 AN: 1111890

Other (OTH) AF: 0.0453 AC: 2734 AN: 60388

GnomAD4 genome AF: 0.0719 AC: 10948 AN: 152194 Hom.: 713 Cov.: 32 AF XY: 0.0688 AC XY: 5123 AN XY: 74412

African (AFR) AF: 0.176 AC: 7286 AN: 41470

American (AMR) AF: 0.0418 AC: 640 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0936 AC: 325 AN: 3472

East Asian (EAS) AF: 0.00501 AC: 26 AN: 5186

South Asian (SAS) AF: 0.0314 AC: 151 AN: 4816

European-Finnish (FIN) AF: 0.00904 AC: 96 AN: 10614

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0328 AC: 2230 AN: 68028

Other (OTH) AF: 0.0736 AC: 155 AN: 2106

Alfa AF: 0.0466 Hom.: 1031

Bravo AF: 0.0801

TwinsUK AF: 0.0297 AC: 110

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.173 AC: 761

ESP6500EA AF: 0.0371 AC: 319

ExAC AF: 0.0454 AC: 5508

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.0371

EpiControl AF: 0.0427

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	0.070
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Benign	0.39
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.35
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.24
Sift	Benign	0.37	T
Sift4G	Uncertain	0.014	D
Polyphen		0.017	B
Vest4		0.13
MPC		0.15
ClinPred		0.010	T
GERP RS		-1.3
Varity_R		0.059
gMVP		0.21
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.090		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: rs36117715; hg19: chr2-238262021; COSMIC: COSV55082067; COSMIC: COSV55082067;