NM_001036.6:c.5834C>T

Variant names:

• chr15-33670530-C-T
• rs375210672
• NM_001036.6:c.5834C>T
• RYR3 p.Pro1945Leu

Variant summary

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

The NM_001036.6(RYR3):​c.5834C>T​(p.Pro1945Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000282 in 1,594,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.20
• 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

ENSG00000295407 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.5834C>T	p.Pro1945Leu	missense	Exon 38 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.5834C>T	p.Pro1945Leu	missense	Exon 38 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.5834C>T	p.Pro1945Leu	missense	Exon 38 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.5834C>T	p.Pro1945Leu	missense	Exon 38 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.5834C>T	p.Pro1945Leu	missense	Exon 38 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

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: 0.00318

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000217 AC: 5 AN: 230266 AF XY: 0.0000240

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: 0.0000468

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 35 AN: 1442500 Hom.: 0 Cov.: 31 AF XY: 0.0000307 AC XY: 22 AN XY: 716942

African (AFR) AF: 0.0000621 AC: 2 AN: 32230

American (AMR) AF: 0.00 AC: 0 AN: 39732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24754

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39560

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52940

Middle Eastern (MID) AF: 0.00124 AC: 7 AN: 5636

European-Non Finnish (NFE) AF: 0.0000190 AC: 21 AN: 1105466

Other (OTH) AF: 0.0000168 AC: 1 AN: 59488

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74370

African (AFR) AF: 0.000217 AC: 9 AN: 41502

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.2
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.34
Sift	Benign	0.18	T
Varity_R		0.22
gMVP		0.38
Mutation Taster		=65/35	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

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

Other links and lift over

dbSNP: rs375210672; hg19: chr15-33962731;