rs375286188

Variant names:

• chr15-33696359-G-A
• rs375286188
• NM_001036.6:c.6002G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-33696359-G-A
• chr15-33696359-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001036.6(RYR3):​c.6002G>A​(p.Arg2001Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R2001R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15928796).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.6002G>A	p.Arg2001Gln	missense	Exon 39 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.6002G>A	p.Arg2001Gln	missense	Exon 39 of 103	NP_001230925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.6002G>A	p.Arg2001Gln	missense	Exon 39 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.6002G>A	p.Arg2001Gln	missense	Exon 39 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.6002G>A	p.Arg2001Gln	missense	Exon 39 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151464 Hom.: 0 Cov.: 31

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000762 AC: 19 AN: 249248 AF XY: 0.0000740

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461700 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44724

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53394

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111866

Other (OTH) AF: 0.0000331 AC: 2 AN: 60374

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151464 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73970

African (AFR) AF: 0.00 AC: 0 AN: 41146

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67868

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000660 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.046
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.048
Sift	Benign	0.44	T
Polyphen		0.88	P
Vest4		0.53
MVP		0.62
MPC		0.27
ClinPred		0.023	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.35
Mutation Taster		=77/23	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: rs375286188; hg19: chr15-33988560; COSMIC: COSV105326375;