rs59021219

chr15-33662563-A-G

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.5033A>G(p.Asp1678Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00632 in 1,613,842 control chromosomes in the GnomAD database, including 534 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.034 (281 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (253 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.95

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=0.0017106831).
• BP6: Variant 15-33662563-A-G is Benign according to our data. Variant chr15-33662563-A-G is described in ClinVar as [Benign]. Clinvar id is 461920.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.5033A>G	p.Asp1678Gly	missense_variant	35/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.5033A>G	p.Asp1678Gly	missense_variant	35/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.5033A>G	p.Asp1678Gly	missense_variant	35/104	5		A1
RYR3	ENST00000415757.7	c.5033A>G	p.Asp1678Gly	missense_variant	35/103	2		A2
RYR3	ENST00000634418.1	c.5033A>G	p.Asp1678Gly	missense_variant	35/102	5

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5108 AN: 152016 Hom.: 282 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.0210

GnomAD3 exomes AF: 0.00896 AC: 2233 AN: 249294 Hom.: 122 AF XY: 0.00665 AC XY: 899 AN XY: 135248

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.00637

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000522

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00348 AC: 5082 AN: 1461708 Hom.: 253 Cov.: 36 AF XY: 0.00295 AC XY: 2142 AN XY: 727136

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.00742

Gnomad4 ASJ exome AF: 0.00417

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000330

Gnomad4 OTH exome AF: 0.00745

GnomAD4 genome AF: 0.0336 AC: 5114 AN: 152134 Hom.: 281 Cov.: 32 AF XY: 0.0320 AC XY: 2376 AN XY: 74356

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000721

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.00620 Hom.: 62

Bravo AF: 0.0389

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.114 AC: 453

ESP6500EA AF: 0.000602 AC: 5

ExAC AF: 0.0106 AC: 1283

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000593

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 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Benign	0.79
DEOGEN2	Benign	0.38	T;.;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T;T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;.;.;.
MutationTaster	Benign	0.80	D;D
PrimateAI	Benign	0.38	T
Polyphen		0.081	B;B;.;.;.
Vest4		0.17
MPC		0.25
ClinPred		0.017	T
GERP RS		5.2
Varity_R		0.19
gMVP		0.45

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: rs59021219; hg19: chr15-33954764;