rs2278309

Variant names:

• chr15-33750626-T-C
• rs2278309
• NM_001036.6:c.8399+340T>C

Variant summary

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

The NM_001036.6(RYR3):​c.8399+340T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 152,178 control chromosomes in the GnomAD database, including 49,580 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 0.81 (49580 hom., cov: 33)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.727
• Publications: 5 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.8399+340T>C		intron_variant	Intron 57 of 103	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.8399+340T>C		intron_variant	Intron 57 of 103	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122637 AN: 152060 Hom.: 49548 Cov.: 33

Gnomad AFR AF: 0.844

Gnomad AMI AF: 0.710

Gnomad AMR AF: 0.847

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.799

Gnomad OTH AF: 0.798

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

GnomAD4 genome AF: 0.806 AC: 122728 AN: 152178 Hom.: 49580 Cov.: 33 AF XY: 0.806 AC XY: 59982 AN XY: 74398

African (AFR) AF: 0.844 AC: 35016 AN: 41510

American (AMR) AF: 0.847 AC: 12954 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 2443 AN: 3470

East Asian (EAS) AF: 0.670 AC: 3467 AN: 5176

South Asian (SAS) AF: 0.727 AC: 3509 AN: 4824

European-Finnish (FIN) AF: 0.802 AC: 8482 AN: 10580

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.799 AC: 54333 AN: 68004

Other (OTH) AF: 0.793 AC: 1674 AN: 2110

Alfa AF: 0.807 Hom.: 43099

Bravo AF: 0.813

Asia WGS AF: 0.709 AC: 2463 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.51
PhyloP100		-0.73
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: rs2278309; hg19: chr15-34042827;