rs114825824

Positions:

• chr15-33601458-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001036.6(RYR3):​c.1828G>A​(p.Val610Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,094 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (15 hom., cov: 31)
  • Exomes 𝑓: 0.00077 (13 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.10

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=0.013581127).
• BP6: Variant 15-33601458-G-A is Benign according to our data. Variant chr15-33601458-G-A is described in ClinVar as [Benign]. Clinvar id is 461886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-33601458-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00681 (1037/152236) while in subpopulation AFR AF= 0.024 (996/41530). AF 95% confidence interval is 0.0227. There are 15 homozygotes in gnomad4. There are 476 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6	c.1828G>A	p.Val610Ile	missense_variant	17/104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.1828G>A	p.Val610Ile	missense_variant	17/104	1	NM_001036.6	ENSP00000489262	P4
RYR3	ENST00000389232.9	c.1828G>A	p.Val610Ile	missense_variant	17/104	5		ENSP00000373884	A1
RYR3	ENST00000415757.7	c.1828G>A	p.Val610Ile	missense_variant	17/103	2		ENSP00000399610	A2
RYR3	ENST00000634418.1	c.1828G>A	p.Val610Ile	missense_variant	17/102	5		ENSP00000489529

Frequencies

GnomAD3 genomes AF: 0.00682 AC: 1037 AN: 152118 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00170 AC: 421 AN: 248008 Hom.: 5 AF XY: 0.00126 AC XY: 170 AN XY: 134542

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.000844

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000767 AC: 1120 AN: 1460858 Hom.: 13 Cov.: 31 AF XY: 0.000736 AC XY: 535 AN XY: 726658

Gnomad4 AFR exome AF: 0.0264

Gnomad4 AMR exome AF: 0.000963

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.000895

GnomAD4 genome AF: 0.00681 AC: 1037 AN: 152236 Hom.: 15 Cov.: 31 AF XY: 0.00639 AC XY: 476 AN XY: 74438

Gnomad4 AFR AF: 0.0240

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00149 Hom.: 2

Bravo AF: 0.00743

ESP6500AA AF: 0.0198 AC: 82

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00208 AC: 252

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000238

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

Dec 11, 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	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
MetaRNN	Benign	0.014	T;T;T;T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.76	.;N;N;.;.
REVEL	Uncertain	0.63
Sift	Benign	0.12	.;T;T;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.45
MVP		0.79
MPC		0.66
ClinPred		0.029	T
GERP RS		4.6
Varity_R		0.12
gMVP		0.50

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: rs114825824; hg19: chr15-33893659;