rs201215774

Variant names:

• chr15-33613232-G-A
• rs201215774
• NM_001036.6:c.2214G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-33613232-G-A
• chr15-33613232-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001036.6(RYR3):​c.2214G>A​(p.Ser738Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,892 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.55
• 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: G2P, ClinGen
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-33613232-G-A is Benign according to our data. Variant chr15-33613232-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 461889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.55 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.2214G>A	p.Ser738Ser	synonymous	Exon 19 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.2214G>A	p.Ser738Ser	synonymous	Exon 19 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.2214G>A	p.Ser738Ser	synonymous	Exon 19 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.2214G>A	p.Ser738Ser	synonymous	Exon 19 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.2214G>A	p.Ser738Ser	synonymous	Exon 19 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00100 AC: 250 AN: 248890 AF XY: 0.00102

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00148 AC: 2165 AN: 1461582 Hom.: 6 Cov.: 32 AF XY: 0.00141 AC XY: 1026 AN XY: 727056

African (AFR) AF: 0.000269 AC: 9 AN: 33474

American (AMR) AF: 0.000649 AC: 29 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86224

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53398

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

European-Non Finnish (NFE) AF: 0.00177 AC: 1963 AN: 1111814

Other (OTH) AF: 0.00126 AC: 76 AN: 60368

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74484

African (AFR) AF: 0.000361 AC: 15 AN: 41568

American (AMR) AF: 0.000915 AC: 14 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00173 AC: 118 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00107

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00160

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

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
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.076
DANN	Benign	0.62
PhyloP100		-3.6
Mutation Taster		=88/12	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: rs201215774; hg19: chr15-33905433; COSMIC: COSV66785968;