rs2229116

chr15-33613209-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.2191A>G(p.Ile731Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,612,830 control chromosomes in the GnomAD database, including 40,692 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.21 (3393 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37299 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.446

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=0.0047627687).
• BP6: Variant 15-33613209-A-G is Benign according to our data. Variant chr15-33613209-A-G is described in ClinVar as [Benign]. Clinvar id is 1166904.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.2191A>G	p.Ile731Val	missense_variant	19/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.2191A>G	p.Ile731Val	missense_variant	19/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.2191A>G	p.Ile731Val	missense_variant	19/104	5		A1
RYR3	ENST00000415757.7	c.2191A>G	p.Ile731Val	missense_variant	19/103	2		A2
RYR3	ENST00000634418.1	c.2191A>G	p.Ile731Val	missense_variant	19/102	5

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31366 AN: 151930 Hom.: 3386 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.191

GnomAD3 exomes AF: 0.230 AC: 56968 AN: 247702 Hom.: 6925 AF XY: 0.228 AC XY: 30700 AN XY: 134480

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.320

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.156

Gnomad SAS exome AF: 0.243

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.223 AC: 325218 AN: 1460780 Hom.: 37299 Cov.: 33 AF XY: 0.223 AC XY: 161949 AN XY: 726660

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.179

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.284

Gnomad4 NFE exome AF: 0.220

Gnomad4 OTH exome AF: 0.213

GnomAD4 genome AF: 0.207 AC: 31408 AN: 152050 Hom.: 3393 Cov.: 32 AF XY: 0.211 AC XY: 15690 AN XY: 74330

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.241

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.193

Alfa AF: 0.211 Hom.: 9079

Bravo AF: 0.203

TwinsUK AF: 0.226 AC: 837

ALSPAC AF: 0.233 AC: 899

ESP6500AA AF: 0.138 AC: 576

ESP6500EA AF: 0.215 AC: 1824

ExAC AF: 0.226 AC: 27333

Asia WGS AF: 0.215 AC: 747 AN: 3478

EpiCase AF: 0.208

EpiControl AF: 0.208

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

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	16
Dann	Benign	0.90
DEOGEN2	Benign	0.23	T;.;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.76	T;T;T;T;T
MetaRNN	Benign	0.0048	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;N;.;.;.
MutationTaster	Benign	0.96	P;P
PrimateAI	Benign	0.41	T
Polyphen		0.0	B;B;.;.;.
Vest4		0.041
MPC		0.15
ClinPred		0.0042	T
GERP RS		3.1
Varity_R		0.023
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2229116; hg19: chr15-33905410; COSMIC: COSV66780635;