15-33362416-G-T

Variant names:

• chr15-33362416-G-T
• rs2676035
• NM_001036.6:c.51+51320G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001036.6(RYR3):​c.51+51320G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 149,128 control chromosomes in the GnomAD database, including 20,548 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.52 (20548 hom., cov: 27)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 1 publications found

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]

RYR3 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.51+51320G>T		intron	N/A	NP_001027.3
	RYR3	NM_001243996.4		c.51+51320G>T		intron	N/A	NP_001230925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.51+51320G>T		intron	N/A	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.51+51320G>T		intron	N/A	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.51+51320G>T		intron	N/A	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.524 AC: 78147 AN: 149014 Hom.: 20538 Cov.: 27

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.495

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.524 AC: 78205 AN: 149128 Hom.: 20548 Cov.: 27 AF XY: 0.524 AC XY: 38143 AN XY: 72800

African (AFR) AF: 0.473 AC: 18962 AN: 40102

American (AMR) AF: 0.502 AC: 7535 AN: 15004

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 2017 AN: 3438

East Asian (EAS) AF: 0.664 AC: 3361 AN: 5058

South Asian (SAS) AF: 0.538 AC: 2518 AN: 4684

European-Finnish (FIN) AF: 0.565 AC: 5838 AN: 10340

Middle Eastern (MID) AF: 0.503 AC: 145 AN: 288

European-Non Finnish (NFE) AF: 0.539 AC: 36268 AN: 67242

Other (OTH) AF: 0.494 AC: 1022 AN: 2068

Alfa AF: 0.422 Hom.: 1254

Bravo AF: 0.515

Asia WGS AF: 0.560 AC: 1946 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.25
DANN	Benign	0.46
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2676035; hg19: chr15-33654617; COSMIC: COSV66809228;