15-33625741-T-C

Variant names:

• chr15-33625741-T-C
• rs951442
• NM_001036.6:c.2574+1718T>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.2574+1718T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 151,872 control chromosomes in the GnomAD database, including 12,657 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 0.40 (12657 hom., cov: 31)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.138
• Publications: 6 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 (EAS) allele frequency at 95% confidence interval = 0.578 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.2574+1718T>C		intron	N/A	NP_001027.3
	RYR3	NM_001243996.4		c.2574+1718T>C		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.2574+1718T>C		intron	N/A	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.2574+1718T>C		intron	N/A	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.2574+1718T>C		intron	N/A	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.402 AC: 60954 AN: 151752 Hom.: 12647 Cov.: 31

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.374

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

GnomAD4 genome AF: 0.402 AC: 60998 AN: 151872 Hom.: 12657 Cov.: 31 AF XY: 0.408 AC XY: 30257 AN XY: 74230

African (AFR) AF: 0.313 AC: 12957 AN: 41378

American (AMR) AF: 0.462 AC: 7061 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1101 AN: 3466

East Asian (EAS) AF: 0.595 AC: 3064 AN: 5146

South Asian (SAS) AF: 0.480 AC: 2308 AN: 4812

European-Finnish (FIN) AF: 0.483 AC: 5089 AN: 10546

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 28008 AN: 67936

Other (OTH) AF: 0.381 AC: 805 AN: 2114

Alfa AF: 0.407 Hom.: 8419

Bravo AF: 0.396

Asia WGS AF: 0.541 AC: 1880 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.8
DANN	Benign	0.56
PhyloP100		-0.14
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: rs951442; hg19: chr15-33917942;