rs200281542

Variant names:

• chr15-33841977-C-T
• rs200281542
• NM_001036.6:c.13151C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001036.6(RYR3):​c.13151C>T​(p.Pro4384Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000179 in 1,603,396 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 Benign (★). Synonymous variant affecting the same amino acid position (i.e. P4384P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.98
• Publications: 7 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024608195).
• BP6: Variant 15-33841977-C-T is Benign according to our data. Variant chr15-33841977-C-T is described in ClinVar as Benign. ClinVar VariationId is 461860.Status of the report is criteria_provided_single_submitter, 1 stars.

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.13151C>T	p.Pro4384Leu	missense	Exon 91 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.13136C>T	p.Pro4379Leu	missense	Exon 90 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.13151C>T	p.Pro4384Leu	missense	Exon 91 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.13148C>T	p.Pro4383Leu	missense	Exon 91 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.13136C>T	p.Pro4379Leu	missense	Exon 90 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000384 AC: 89 AN: 231470 AF XY: 0.000392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000335

Gnomad ASJ exome AF: 0.00575

Gnomad EAS exome AF: 0.0000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000174 AC: 253 AN: 1451126 Hom.: 1 Cov.: 30 AF XY: 0.000172 AC XY: 124 AN XY: 720626

African (AFR) AF: 0.00 AC: 0 AN: 33322

American (AMR) AF: 0.000276 AC: 12 AN: 43446

Ashkenazi Jewish (ASJ) AF: 0.00594 AC: 153 AN: 25776

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.0000595 AC: 5 AN: 84010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52608

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5658

European-Non Finnish (NFE) AF: 0.0000398 AC: 44 AN: 1106822

Other (OTH) AF: 0.000633 AC: 38 AN: 60008

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74428

African (AFR) AF: 0.0000241 AC: 1 AN: 41562

American (AMR) AF: 0.000327 AC: 5 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000484 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.000290 AC: 35

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.025	T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.0
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.71
Sift	Benign	0.054	T
Sift4G	Benign	0.77	T
Polyphen		0.98	D
Vest4		0.43
MVP		0.79
MPC		0.24
ClinPred		0.078	T
GERP RS		4.4
PromoterAI		-0.089	Neutral
Varity_R		0.15
gMVP		0.44
Mutation Taster		=97/3	polymorphism

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: rs200281542; hg19: chr15-34134178; COSMIC: COSV66786591; COSMIC: COSV66786591;