rs2304380

Positions:

• chr15-33562937-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001036.6(RYR3):​c.1073T>C​(p.Ile358Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00241 in 1,613,838 control chromosomes in the GnomAD database, including 155 homozygotes. 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0033 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (134 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.19

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031332076).
• BP6: Variant 15-33562937-T-C is Benign according to our data. Variant chr15-33562937-T-C is described in ClinVar as [Benign]. Clinvar id is 461830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6	c.1073T>C	p.Ile358Thr	missense_variant	11/104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.1073T>C	p.Ile358Thr	missense_variant	11/104	1	NM_001036.6	ENSP00000489262	P4
RYR3	ENST00000389232.9	c.1073T>C	p.Ile358Thr	missense_variant	11/104	5		ENSP00000373884	A1
RYR3	ENST00000415757.7	c.1073T>C	p.Ile358Thr	missense_variant	11/103	2		ENSP00000399610	A2
RYR3	ENST00000634418.1	c.1073T>C	p.Ile358Thr	missense_variant	11/102	5		ENSP00000489529

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 495 AN: 152194 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0818

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00622 AC: 1550 AN: 249076 Hom.: 65 AF XY: 0.00576 AC XY: 779 AN XY: 135136

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0810

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000886

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00232 AC: 3396 AN: 1461526 Hom.: 134 Cov.: 30 AF XY: 0.00233 AC XY: 1692 AN XY: 727056

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0721

Gnomad4 SAS exome AF: 0.00231

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.00326 AC: 496 AN: 152312 Hom.: 21 Cov.: 33 AF XY: 0.00349 AC XY: 260 AN XY: 74486

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0820

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00227 Hom.: 21

Bravo AF: 0.00365

ESP6500AA AF: 0.000264 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00614 AC: 742

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;.;.;.;.
Eigen	Benign	-0.068
Eigen_PC	Benign	0.076
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T;T;T;T;T
MetaRNN	Benign	0.0031	T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.55	N;N;.;.;.
MutationTaster	Benign	0.66	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	.;N;N;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.038	.;D;D;.;.
Polyphen		0.0	B;B;.;.;.
Vest4		0.35
MVP		0.38
MPC		0.24
ClinPred		0.051	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2304380; hg19: chr15-33855138;