rs61996324

chr15-33660274-C-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.4473C>T(p.Asp1491=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,558,636 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (13 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.82

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=-0.66).
• BP6: Variant 15-33660274-C-T is Benign according to our data. Variant chr15-33660274-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 461913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.82 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.4473C>T	p.Asp1491=	synonymous_variant	34/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.4473C>T	p.Asp1491=	synonymous_variant	34/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.4473C>T	p.Asp1491=	synonymous_variant	34/104	5		A1
RYR3	ENST00000415757.7	c.4473C>T	p.Asp1491=	synonymous_variant	34/103	2		A2
RYR3	ENST00000634418.1	c.4473C>T	p.Asp1491=	synonymous_variant	34/102	5

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 387 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00218 AC: 363 AN: 166426 Hom.: 1 AF XY: 0.00226 AC XY: 200 AN XY: 88322

Gnomad AFR exome AF: 0.000917

Gnomad AMR exome AF: 0.000513

Gnomad ASJ exome AF: 0.000346

Gnomad EAS exome AF: 0.0000869

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00391

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00370 AC: 5207 AN: 1406306 Hom.: 13 Cov.: 32 AF XY: 0.00366 AC XY: 2539 AN XY: 694240

Gnomad4 AFR exome AF: 0.000501

Gnomad4 AMR exome AF: 0.000908

Gnomad4 ASJ exome AF: 0.000158

Gnomad4 EAS exome AF: 0.0000276

Gnomad4 SAS exome AF: 0.00135

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00444

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74482

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00385

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00332 Hom.: 1

Bravo AF: 0.00267

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

Jan 15, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

RYR3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.54
Dann	Benign	0.71

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: rs61996324; hg19: chr15-33952475; COSMIC: COSV66799902;