rs139287308

chr15-33726433-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001036.6(RYR3):c.6960G>C(p.Leu2320=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00044 in 1,611,974 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2320L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00071 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (6 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.142

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 15-33726433-G-C is Benign according to our data. Variant chr15-33726433-G-C is described in ClinVar as [Benign]. Clinvar id is 461942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.142 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000709 (108/152316) while in subpopulation EAS AF= 0.0197 (102/5176). AF 95% confidence interval is 0.0166. There are 2 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.6960G>C	p.Leu2320=	synonymous_variant	46/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.6960G>C	p.Leu2320=	synonymous_variant	46/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152198 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00154 AC: 377 AN: 244868 Hom.: 4 AF XY: 0.00159 AC XY: 211 AN XY: 132624

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0200

Gnomad SAS exome AF: 0.000506

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000412 AC: 602 AN: 1459658 Hom.: 6 Cov.: 31 AF XY: 0.000460 AC XY: 334 AN XY: 725784

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0122

Gnomad4 SAS exome AF: 0.000666

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000929

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152316 Hom.: 2 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0197

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000620

Asia WGS AF: 0.00924 AC: 32 AN: 3478

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

Invitae

Nov 15, 2022

- -

RYR3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	2.2
Dann	Benign	0.82

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: rs139287308; hg19: chr15-34018634; COSMIC: COSV63109824; COSMIC: COSV63109824;