rs2229119

Variant names:

• chr15-33629953-A-G
• rs2229119
• NM_001036.6:c.2693A>G
• RYR3 p.Asn898Ser

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001036.6(RYR3):​c.2693A>G​(p.Asn898Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0016 in 1,599,656 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N898D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.08
• Publications: 5 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01195538).
• BP6: Variant 15-33629953-A-G is Benign according to our data. Variant chr15-33629953-A-G is described in ClinVar as Benign. ClinVar VariationId is 461896.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

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.2693A>G	p.Asn898Ser	missense	Exon 22 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.2693A>G	p.Asn898Ser	missense	Exon 22 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.2693A>G	p.Asn898Ser	missense	Exon 22 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.2693A>G	p.Asn898Ser	missense	Exon 22 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.2693A>G	p.Asn898Ser	missense	Exon 22 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 223 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00154 AC: 359 AN: 233406 AF XY: 0.00149

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.000860

Gnomad ASJ exome AF: 0.000724

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00790

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000865

GnomAD4 exome AF: 0.00162 AC: 2342 AN: 1447292 Hom.: 3 Cov.: 28 AF XY: 0.00161 AC XY: 1158 AN XY: 718868

African (AFR) AF: 0.000271 AC: 9 AN: 33198

American (AMR) AF: 0.00102 AC: 44 AN: 43132

Ashkenazi Jewish (ASJ) AF: 0.000891 AC: 23 AN: 25808

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83180

European-Finnish (FIN) AF: 0.00722 AC: 383 AN: 53064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00165 AC: 1816 AN: 1103728

Other (OTH) AF: 0.00110 AC: 66 AN: 59950

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.00169 AC XY: 126 AN XY: 74504

African (AFR) AF: 0.000337 AC: 14 AN: 41580

American (AMR) AF: 0.00131 AC: 20 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00678 AC: 72 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00166 AC: 113 AN: 68046

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.000956

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

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	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.70	N
PhyloP100		7.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.55
Sift	Benign	0.66	T
Varity_R		0.59
gMVP		0.16
Mutation Taster		=63/37	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: rs2229119;

hg19: chr15-33922154;