rs201633619

Positions:

• chr15-33722741-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001036.6(RYR3):​c.6646G>A​(p.Val2216Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,612,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.13

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28859815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.6646G>A	p.Val2216Ile	missense_variant	44/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.6646G>A	p.Val2216Ile	missense_variant	44/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.6646G>A	p.Val2216Ile	missense_variant	44/104	5		A1
RYR3	ENST00000415757.7	c.6646G>A	p.Val2216Ile	missense_variant	44/103	2		A2
RYR3	ENST00000634418.1	c.6646G>A	p.Val2216Ile	missense_variant	44/102	5

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000162 AC: 4 AN: 247428 Hom.: 0 AF XY: 0.0000298 AC XY: 4 AN XY: 134334

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1460286 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 726452

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74352

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000373 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.000743 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2020

This sequence change replaces valine with isoleucine at codon 2216 of the RYR3 protein (p.Val2216Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs201633619, ExAC 0.03%). This variant has not been reported in the literature in individuals with RYR3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.9	L;L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
Polyphen		1.0	D;P;.;.;.
Vest4		0.46
MVP		0.76
MPC		0.63
ClinPred		0.36	T
GERP RS		4.9
Varity_R		0.22
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs201633619; hg19: chr15-34014942; COSMIC: COSV63109453; COSMIC: COSV63109453;