NM_001036.6:c.592A>G

Variant names:

• chr15-33540836-A-G
• rs139577597
• NM_001036.6:c.592A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001036.6(RYR3):​c.592A>G​(p.Met198Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.05
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39984787).

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.592A>G	p.Met198Val	missense	Exon 7 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.592A>G	p.Met198Val	missense	Exon 7 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.592A>G	p.Met198Val	missense	Exon 7 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.592A>G	p.Met198Val	missense	Exon 7 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.592A>G	p.Met198Val	missense	Exon 7 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248946 AF XY: 0.00000740

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460790 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726748

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111172

Other (OTH) AF: 0.0000166 AC: 1 AN: 60332

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74474

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Epileptic encephalopathy (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.40	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.68
Sift	Benign	0.18	T
Polyphen		0.14	B
Vest4		0.40
MVP		0.81
MPC		0.23
ClinPred		0.61	D
GERP RS		4.6
Varity_R		0.38
gMVP		0.68
Mutation Taster		=61/39	polymorphism

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: rs139577597; hg19: chr15-33833037;