15-33838496-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.12516G>C(p.Val4172=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0368 in 1,613,970 control chromosomes in the GnomAD database, including 1,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (160 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1288 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.578

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=-0.57).
• BP6: Variant 15-33838496-G-C is Benign according to our data. Variant chr15-33838496-G-C is described in ClinVar as [Benign]. Clinvar id is 461852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-33838496-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.578 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0322 (4902/152292) while in subpopulation NFE AF= 0.0385 (2619/68024). AF 95% confidence interval is 0.0373. There are 160 homozygotes in gnomad4. There are 2623 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 160 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.12516G>C	p.Val4172=	synonymous_variant	89/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.12516G>C	p.Val4172=	synonymous_variant	89/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4906 AN: 152174 Hom.: 160 Cov.: 32

Gnomad AFR AF: 0.00695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0385

Gnomad OTH AF: 0.0278

GnomAD3 exomes AF: 0.0350 AC: 8720 AN: 248932 Hom.: 274 AF XY: 0.0355 AC XY: 4792 AN XY: 135070

Gnomad AFR exome AF: 0.00672

Gnomad AMR exome AF: 0.0216

Gnomad ASJ exome AF: 0.0313

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0129

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0389

Gnomad OTH exome AF: 0.0463

GnomAD4 exome AF: 0.0373 AC: 54460 AN: 1461678 Hom.: 1288 Cov.: 33 AF XY: 0.0363 AC XY: 26428 AN XY: 727120

Gnomad4 AFR exome AF: 0.00526

Gnomad4 AMR exome AF: 0.0223

Gnomad4 ASJ exome AF: 0.0325

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0140

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0388

Gnomad4 OTH exome AF: 0.0349

GnomAD4 genome AF: 0.0322 AC: 4902 AN: 152292 Hom.: 160 Cov.: 32 AF XY: 0.0352 AC XY: 2623 AN XY: 74456

Gnomad4 AFR AF: 0.00693

Gnomad4 AMR AF: 0.0285

Gnomad4 ASJ AF: 0.0351

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.0385

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0263 Hom.: 25

Bravo AF: 0.0257

Asia WGS AF: 0.00837 AC: 30 AN: 3478

EpiCase AF: 0.0367

EpiControl AF: 0.0408

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

Jan 15, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.66
Dann	Benign	0.56

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: rs75286462; hg19: chr15-34130697; COSMIC: COSV66789944; COSMIC: COSV66789944;