rs189282419

Variant names:

• chr15-33772059-G-A
• rs189282419
• NM_001036.6:c.8956G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-33772059-G-A
• chr15-33772059-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001036.6(RYR3):​c.8956G>A​(p.Val2986Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,613,686 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 10.0
• Publications: 6 publications found

Genes affected

RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

RYR3 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008155316).
• BP6: Variant 15-33772059-G-A is Benign according to our data. Variant chr15-33772059-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 531158.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.8956G>A	p.Val2986Ile	missense	Exon 63 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.8956G>A	p.Val2986Ile	missense	Exon 63 of 103	NP_001230925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.8956G>A	p.Val2986Ile	missense	Exon 63 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.8953G>A	p.Val2985Ile	missense	Exon 63 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.8956G>A	p.Val2986Ile	missense	Exon 63 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000362 AC: 90 AN: 248788 AF XY: 0.000341

Gnomad AFR exome AF: 0.00466

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000200 AC: 292 AN: 1461446 Hom.: 1 Cov.: 31 AF XY: 0.000180 AC XY: 131 AN XY: 726980

African (AFR) AF: 0.00621 AC: 208 AN: 33474

American (AMR) AF: 0.000224 AC: 10 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39686

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

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

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111744

Other (OTH) AF: 0.000381 AC: 23 AN: 60362

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74448

African (AFR) AF: 0.00563 AC: 234 AN: 41536

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000617 Hom.: 2

Bravo AF: 0.00174

ESP6500AA AF: 0.00287 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000422 AC: 51

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)
-	1	-	not specified (1)
-	-	1	RYR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.0082	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		10
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.47
Sift	Benign	0.074	T
Polyphen		1.0	D
Vest4		0.58
MVP		0.89
MPC		0.62
ClinPred		0.098	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.27
Mutation Taster		=49/51	disease causing

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: rs189282419; hg19: chr15-34064260; COSMIC: COSV66781259;