rs200281542

chr15-33841977-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 461860.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.13151C>T	p.Pro4384Leu	missense_variant	91/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.13151C>T	p.Pro4384Leu	missense_variant	91/104	1	NM_001036.6	P4

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

GnomAD3 exomes AF: 0.000384 AC: 89 AN: 231470 Hom.: 1 AF XY: 0.000392 AC XY: 49 AN XY: 125120

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 SAS exome AF: 0.0000358

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000276

Gnomad4 ASJ exome AF: 0.00594

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000595

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000398

Gnomad4 OTH exome AF: 0.000633

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000518 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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.025	T;T;T;T;T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
Polyphen		0.98	D;P;.;.;.;.
Vest4		0.43
MVP		0.79
MPC		0.24
ClinPred		0.078	T
GERP RS		4.4
Varity_R		0.15
gMVP		0.44

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

Publications

LitVar

Other links and lift over

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