rs148818748

Positions:

• chr15-33662923-G-A
• chr15-33662923-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001036.6(RYR3):​c.5393G>A​(p.Arg1798Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00083 in 1,612,816 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (1 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.30

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033837706).
• BP6: Variant 15-33662923-G-A is Benign according to our data. Variant chr15-33662923-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461926.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6	c.5393G>A	p.Arg1798Gln	missense_variant	35/104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.5393G>A	p.Arg1798Gln	missense_variant	35/104	1	NM_001036.6	ENSP00000489262	P4
RYR3	ENST00000389232.9	c.5393G>A	p.Arg1798Gln	missense_variant	35/104	5		ENSP00000373884	A1
RYR3	ENST00000415757.7	c.5393G>A	p.Arg1798Gln	missense_variant	35/103	2		ENSP00000399610	A2
RYR3	ENST00000634418.1	c.5393G>A	p.Arg1798Gln	missense_variant	35/102	5		ENSP00000489529

Frequencies

GnomAD3 genomes AF: 0.000960 AC: 146 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000796 AC: 197 AN: 247596 Hom.: 0 AF XY: 0.000767 AC XY: 103 AN XY: 134248

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000817 AC: 1193 AN: 1460572 Hom.: 1 Cov.: 36 AF XY: 0.000827 AC XY: 601 AN XY: 726396

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.000171

Gnomad4 NFE exome AF: 0.000928

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000952 AC: 145 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000981 AC XY: 73 AN XY: 74426

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000907 Hom.: 2

Bravo AF: 0.00108

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000246 AC: 1

ESP6500EA AF: 0.000596 AC: 5

ExAC AF: 0.000694 AC: 84

EpiCase AF: 0.00136

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.034	T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.3	L;L;.;.;.
MutationTaster	Benign	0.73	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	.;N;N;.;.
REVEL	Benign	0.069
Sift	Benign	0.089	.;T;T;.;.
Polyphen		0.89	P;P;.;.;.
Vest4		0.56
MVP		0.63
MPC		0.22
ClinPred		0.016	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148818748; hg19: chr15-33955124;