rs187371252

chr15-33663602-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001036.6(RYR3):c.5484A>G(p.Ala1828=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,613,652 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0710

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-33663602-A-G is Benign according to our data. Variant chr15-33663602-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 461929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.071 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.5484A>G	p.Ala1828=	synonymous_variant	36/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.5484A>G	p.Ala1828=	synonymous_variant	36/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.5484A>G	p.Ala1828=	synonymous_variant	36/104	5		A1
RYR3	ENST00000415757.7	c.5484A>G	p.Ala1828=	synonymous_variant	36/103	2		A2
RYR3	ENST00000634418.1	c.5484A>G	p.Ala1828=	synonymous_variant	36/102	5

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00132 AC: 327 AN: 248620 Hom.: 2 AF XY: 0.00125 AC XY: 169 AN XY: 134846

Gnomad AFR exome AF: 0.000455

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000362

Gnomad FIN exome AF: 0.000836

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00190 AC: 2782 AN: 1461380 Hom.: 5 Cov.: 31 AF XY: 0.00180 AC XY: 1310 AN XY: 726894

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00231

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00120 AC: 182 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74464

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00218

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00106

EpiCase AF: 0.00240

EpiControl AF: 0.00196

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

Dec 02, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

RYR3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	6.0
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: rs187371252; hg19: chr15-33955803;