rs2596179

Variant names:

• chr15-33362531-A-C
• rs2596179
• NM_001036.6:c.51+51435A>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.51+51435A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 151,928 control chromosomes in the GnomAD database, including 11,038 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 0.38 (11038 hom., cov: 31)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.672
• Publications: 3 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.51+51435A>C		intron_variant	Intron 1 of 103	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.51+51435A>C		intron_variant	Intron 1 of 103	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57653 AN: 151810 Hom.: 11033 Cov.: 31

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.345

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

GnomAD4 genome AF: 0.380 AC: 57700 AN: 151928 Hom.: 11038 Cov.: 31 AF XY: 0.381 AC XY: 28313 AN XY: 74264

African (AFR) AF: 0.368 AC: 15233 AN: 41426

American (AMR) AF: 0.384 AC: 5865 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1251 AN: 3466

East Asian (EAS) AF: 0.561 AC: 2899 AN: 5172

South Asian (SAS) AF: 0.325 AC: 1564 AN: 4814

European-Finnish (FIN) AF: 0.400 AC: 4215 AN: 10544

Middle Eastern (MID) AF: 0.308 AC: 90 AN: 292

European-Non Finnish (NFE) AF: 0.375 AC: 25497 AN: 67926

Other (OTH) AF: 0.345 AC: 728 AN: 2108

Alfa AF: 0.370 Hom.: 7723

Bravo AF: 0.379

Asia WGS AF: 0.423 AC: 1469 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.0
DANN	Benign	0.76
PhyloP100		0.67
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: rs2596179; hg19: chr15-33654732;