15-33639030-T-C

Variant names:

• chr15-33639030-T-C
• rs10851886
• NM_001036.6:c.3556+2480T>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.3556+2480T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 152,098 control chromosomes in the GnomAD database, including 3,332 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 0.19 (3332 hom., cov: 32)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.470
• Publications: 2 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: G2P, PanelApp Australia, ClinGen
• congenital myopathy

  Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.3556+2480T>C		intron	N/A	NP_001027.3
	RYR3	NM_001243996.4		c.3556+2480T>C		intron	N/A	NP_001230925.1	Q15413-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.3556+2480T>C		intron	N/A	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.3556+2480T>C		intron	N/A	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.3556+2480T>C		intron	N/A	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29388 AN: 151978 Hom.: 3320 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.183

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

GnomAD4 genome AF: 0.193 AC: 29423 AN: 152098 Hom.: 3332 Cov.: 32 AF XY: 0.197 AC XY: 14685 AN XY: 74368

African (AFR) AF: 0.267 AC: 11088 AN: 41476

American (AMR) AF: 0.145 AC: 2218 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 505 AN: 3472

East Asian (EAS) AF: 0.486 AC: 2505 AN: 5150

South Asian (SAS) AF: 0.210 AC: 1011 AN: 4818

European-Finnish (FIN) AF: 0.217 AC: 2300 AN: 10600

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9281 AN: 67978

Other (OTH) AF: 0.187 AC: 395 AN: 2110

Alfa AF: 0.163 Hom.: 774

Bravo AF: 0.194

Asia WGS AF: 0.342 AC: 1186 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.93
DANN	Benign	0.48
PhyloP100		-0.47
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: rs10851886; hg19: chr15-33931231;