rs61996325

chr15-33660412-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001036.6(RYR3):c.4611C>T(p.Pro1537=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,563,356 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.93

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=-0.65).
• BP6: Variant 15-33660412-C-T is Benign according to our data. Variant chr15-33660412-C-T is described in ClinVar as [Benign]. Clinvar id is 531151.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000481 (679/1411076) while in subpopulation AFR AF= 0.0165 (534/32274). AF 95% confidence interval is 0.0154. There are 6 homozygotes in gnomad4_exome. There are 285 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.4611C>T	p.Pro1537=	synonymous_variant	34/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.4611C>T	p.Pro1537=	synonymous_variant	34/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.4611C>T	p.Pro1537=	synonymous_variant	34/104	5		A1
RYR3	ENST00000415757.7	c.4611C>T	p.Pro1537=	synonymous_variant	34/103	2		A2
RYR3	ENST00000634418.1	c.4611C>T	p.Pro1537=	synonymous_variant	34/102	5

Frequencies

GnomAD3 genomes AF: 0.00448 AC: 682 AN: 152162 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00112 AC: 190 AN: 170216 Hom.: 1 AF XY: 0.000803 AC XY: 73 AN XY: 90872

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000880

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.000242

Gnomad SAS exome AF: 0.000696

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000143

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000481 AC: 679 AN: 1411076 Hom.: 6 Cov.: 32 AF XY: 0.000409 AC XY: 285 AN XY: 696688

Gnomad4 AFR exome AF: 0.0165

Gnomad4 AMR exome AF: 0.000906

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000217

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000120

Gnomad4 OTH exome AF: 0.000888

GnomAD4 genome AF: 0.00448 AC: 682 AN: 152280 Hom.: 6 Cov.: 33 AF XY: 0.00381 AC XY: 284 AN XY: 74456

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00514

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.20
Dann	Benign	0.67

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: rs61996325; hg19: chr15-33952613; COSMIC: COSV66801941;