rs772574630

chr15-33660334-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001036.6(RYR3):c.4533G>C(p.Glu1511Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000195 in 1,439,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.484

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18157268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.4533G>C	p.Glu1511Asp	missense_variant	34/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.4533G>C	p.Glu1511Asp	missense_variant	34/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.4533G>C	p.Glu1511Asp	missense_variant	34/104	5		A1
RYR3	ENST00000415757.7	c.4533G>C	p.Glu1511Asp	missense_variant	34/103	2		A2
RYR3	ENST00000634418.1	c.4533G>C	p.Glu1511Asp	missense_variant	34/102	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000195 AC: 28 AN: 1439424 Hom.: 0 Cov.: 32 AF XY: 0.0000154 AC XY: 11 AN XY: 713460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000200

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

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

Mar 04, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). This variant has not been reported in the literature in individuals with RYR3-related conditions. ClinVar contains an entry for this variant (Variation ID: 566062). This variant is present in population databases (rs772574630, ExAC 0.005%). This sequence change replaces glutamic acid with aspartic acid at codon 1511 of the RYR3 protein (p.Glu1511Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	18
Dann	Benign	0.92
DEOGEN2	Benign	0.33	T;.;.;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.80	T;T;T;T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	0.69	N;N;.;.;.
MutationTaster	Benign	0.80	D;D
PrimateAI	Uncertain	0.71	T
Polyphen		0.0	B;B;.;.;.
Vest4		0.40
MutPred		0.30		Loss of methylation at K1509 (P = 0.0823);Loss of methylation at K1509 (P = 0.0823);Loss of methylation at K1509 (P = 0.0823);Loss of methylation at K1509 (P = 0.0823);Loss of methylation at K1509 (P = 0.0823);
MVP		0.43
MPC		0.16
ClinPred		0.042	T
GERP RS		1.9
Varity_R		0.085
gMVP		0.40

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: rs772574630; hg19: chr15-33952535;