rs115321092

chr15-33662829-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001036.6(RYR3):c.5299G>A(p.Glu1767Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00449 in 1,613,938 control chromosomes in the GnomAD database, including 218 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0044 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (201 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.51

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002911806).
• BP6: Variant 15-33662829-G-A is Benign according to our data. Variant chr15-33662829-G-A is described in ClinVar as [Benign]. Clinvar id is 461925.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.5299G>A	p.Glu1767Lys	missense_variant	35/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.5299G>A	p.Glu1767Lys	missense_variant	35/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.5299G>A	p.Glu1767Lys	missense_variant	35/104	5		A1
RYR3	ENST00000415757.7	c.5299G>A	p.Glu1767Lys	missense_variant	35/103	2		A2
RYR3	ENST00000634418.1	c.5299G>A	p.Glu1767Lys	missense_variant	35/102	5

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 679 AN: 152176 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00596

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0679

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00912 AC: 2272 AN: 249228 Hom.: 88 AF XY: 0.0116 AC XY: 1570 AN XY: 135208

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00167

Gnomad SAS exome AF: 0.0636

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000778

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00449 AC: 6567 AN: 1461644 Hom.: 201 Cov.: 36 AF XY: 0.00610 AC XY: 4434 AN XY: 727098

Gnomad4 AFR exome AF: 0.00726

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.0591

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000542

Gnomad4 OTH exome AF: 0.00654

GnomAD4 genome AF: 0.00441 AC: 672 AN: 152294 Hom.: 17 Cov.: 32 AF XY: 0.00545 AC XY: 406 AN XY: 74466

Gnomad4 AFR AF: 0.00592

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0667

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00153 Hom.: 3

Bravo AF: 0.00279

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00482 AC: 20

ESP6500EA AF: 0.000593 AC: 5

ExAC AF: 0.0103 AC: 1242

Asia WGS AF: 0.0440 AC: 153 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00119

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

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.;.;.
Eigen	Benign	0.0060
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L;L;.;.;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.51	T
Polyphen		0.0	B;B;.;.;.
Vest4		0.41
MPC		0.21
ClinPred		0.017	T
GERP RS		5.1
Varity_R		0.22
gMVP		0.38

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: rs115321092; hg19: chr15-33955030;