rs199553688

chr15-33861083-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001036.6(RYR3):c.14370A>G(p.Lys4790=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000915 in 1,584,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.11

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]

(HGNC:):

AVEN (HGNC:13509): (apoptosis and caspase activation inhibitor) Involved in negative regulation of apoptotic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 15-33861083-A-G is Benign according to our data. Variant chr15-33861083-A-G is described in ClinVar as [Benign]. Clinvar id is 531162.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.11 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.14370A>G	p.Lys4790=	synonymous_variant	102/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.14370A>G	p.Lys4790=	synonymous_variant	102/104	1	NM_001036.6	P4
	ENST00000560268.2	n.70-1989T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152182 Hom.: 0 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: 0.00173

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000236 AC: 49 AN: 207428 Hom.: 0 AF XY: 0.000253 AC XY: 28 AN XY: 110734

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00200

Gnomad SAS exome AF: 0.000466

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.0000887 AC: 127 AN: 1431714 Hom.: 0 Cov.: 30 AF XY: 0.0000945 AC XY: 67 AN XY: 709006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000249

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00131

Gnomad4 SAS exome AF: 0.000416

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000320

Gnomad4 OTH exome AF: 0.0000842

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000125

Asia WGS AF: 0.00231 AC: 8 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

Jun 13, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	2.9
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199553688; hg19: chr15-34153284;