rs1462237800

Variant names:

• chr15-33707036-T-C
• rs1462237800
• NM_001036.6:c.6601T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001036.6(RYR3):​c.6601T>C​(p.Phe2201Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.6601T>C	p.Phe2201Leu	missense_variant	Exon 43 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.6601T>C	p.Phe2201Leu	missense_variant	Exon 43 of 104	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9	c.6601T>C	p.Phe2201Leu	missense_variant	Exon 43 of 104	5		ENSP00000373884.5
RYR3	ENST00000415757.7	c.6601T>C	p.Phe2201Leu	missense_variant	Exon 43 of 103	2		ENSP00000399610.3
RYR3	ENST00000634418.1	c.6601T>C	p.Phe2201Leu	missense_variant	Exon 43 of 102	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 249024 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00000205 AC: 3 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727098

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111828

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

Dec 27, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with RYR3-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 2201 of the RYR3 protein (p.Phe2201Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.3	.;D;D;.;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0080	.;D;D;.;.
Polyphen		1.0	D;P;.;.;.
Vest4		0.90
MutPred		0.59		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.95
MPC		0.79
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.79
Mutation Taster		=33/67	disease causing

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: rs1462237800; hg19: chr15-33999237; COSMIC: COSV107491227;