rs597566

Variant names:

• chr15-33592422-A-T
• rs597566
• NM_001036.6:c.1788+6306A>T

Variant summary

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

The NM_001036.6(RYR3):​c.1788+6306A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 152,038 control chromosomes in the GnomAD database, including 36,252 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 0.69 (36252 hom., cov: 31)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.363
• 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: PanelApp Australia, ClinGen, G2P
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.804 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.1788+6306A>T		intron	N/A	NP_001027.3
	RYR3	NM_001243996.4		c.1788+6306A>T		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.1788+6306A>T		intron	N/A	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.1788+6306A>T		intron	N/A	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.1788+6306A>T		intron	N/A	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.686 AC: 104191 AN: 151920 Hom.: 36220 Cov.: 31

Gnomad AFR AF: 0.812

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.653

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

GnomAD4 genome AF: 0.686 AC: 104279 AN: 152038 Hom.: 36252 Cov.: 31 AF XY: 0.679 AC XY: 50502 AN XY: 74328

African (AFR) AF: 0.811 AC: 33669 AN: 41490

American (AMR) AF: 0.615 AC: 9396 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2295 AN: 3472

East Asian (EAS) AF: 0.764 AC: 3942 AN: 5162

South Asian (SAS) AF: 0.579 AC: 2784 AN: 4810

European-Finnish (FIN) AF: 0.586 AC: 6183 AN: 10556

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.645 AC: 43818 AN: 67958

Other (OTH) AF: 0.653 AC: 1378 AN: 2110

Alfa AF: 0.671 Hom.: 4282

Bravo AF: 0.693

Asia WGS AF: 0.682 AC: 2372 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.81
DANN	Benign	0.35
PhyloP100		-0.36
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs597566;

hg19: chr15-33884623;