15-33768658-C-T

Variant names:

• chr15-33768658-C-T
• rs774409645
• NM_001036.6:c.8706C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The NM_001036.6(RYR3):​c.8706C>T​(p.Gly2902Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G2902G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: RYR3 NM_001036.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.04248
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• 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: G2P, PanelApp Australia, ClinGen
• congenital myopathy

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP7: Synonymous conserved (PhyloP=2.23 with no splicing effect.

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.8706C>T	p.Gly2902Gly	splice_region synonymous	Exon 61 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.8706C>T	p.Gly2902Gly	splice_region synonymous	Exon 61 of 103	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.8706C>T	p.Gly2902Gly	splice_region synonymous	Exon 61 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.8703C>T	p.Gly2901Gly	splice_region synonymous	Exon 61 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.8706C>T	p.Gly2902Gly	splice_region synonymous	Exon 61 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 249198 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461596 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727082

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111778

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.042
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.16		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: rs774409645; hg19: chr15-34060859;