rs201215774

chr15-33613232-G-Achr15-33613232-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001036.6(RYR3):c.2214G>A(p.Ser738=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,892 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.55

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-33613232-G-A is Benign according to our data. Variant chr15-33613232-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 461889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.55 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.2214G>A	p.Ser738=	synonymous_variant	19/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.2214G>A	p.Ser738=	synonymous_variant	19/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.2214G>A	p.Ser738=	synonymous_variant	19/104	5		A1
RYR3	ENST00000415757.7	c.2214G>A	p.Ser738=	synonymous_variant	19/103	2		A2
RYR3	ENST00000634418.1	c.2214G>A	p.Ser738=	synonymous_variant	19/102	5

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00100 AC: 250 AN: 248890 Hom.: 0 AF XY: 0.00102 AC XY: 138 AN XY: 135052

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00148 AC: 2165 AN: 1461582 Hom.: 6 Cov.: 32 AF XY: 0.00141 AC XY: 1026 AN XY: 727056

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00177

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74484

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00173

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00107

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00160

ClinVar

Significance: Benign/Likely 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

Invitae

Oct 11, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

RYR3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.076
Dann	Benign	0.62

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: rs201215774; hg19: chr15-33905433; COSMIC: COSV66785968;