rs200740143

Variant names:

• chr15-33662351-T-C
• rs200740143
• NM_001036.6:c.4821T>C

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.4821T>C​(p.Tyr1607Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,612,820 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (11 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.771
• 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: ClinGen, G2P
• 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=-0.52).
• BP6: Variant 15-33662351-T-C is Benign according to our data. Variant chr15-33662351-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 461919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.771 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 11 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.4821T>C	p.Tyr1607Tyr	synonymous	Exon 35 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.4821T>C	p.Tyr1607Tyr	synonymous	Exon 35 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.4821T>C	p.Tyr1607Tyr	synonymous	Exon 35 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.4821T>C	p.Tyr1607Tyr	synonymous	Exon 35 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.4821T>C	p.Tyr1607Tyr	synonymous	Exon 35 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 261 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00287

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00188 AC: 464 AN: 246396 AF XY: 0.00196

Gnomad AFR exome AF: 0.000401

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.000903

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000605

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00280 AC: 4091 AN: 1460448 Hom.: 11 Cov.: 31 AF XY: 0.00274 AC XY: 1991 AN XY: 726362

African (AFR) AF: 0.000508 AC: 17 AN: 33456

American (AMR) AF: 0.00164 AC: 73 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.000959 AC: 25 AN: 26078

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

South Asian (SAS) AF: 0.0000932 AC: 8 AN: 85848

European-Finnish (FIN) AF: 0.000637 AC: 34 AN: 53356

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00342 AC: 3800 AN: 1111434

Other (OTH) AF: 0.00215 AC: 130 AN: 60340

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74512

African (AFR) AF: 0.000577 AC: 24 AN: 41592

American (AMR) AF: 0.00131 AC: 20 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00287 AC: 195 AN: 68042

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00232 Hom.: 0

Bravo AF: 0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR3: BP4, BP7

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.9
DANN	Benign	0.47
PhyloP100		0.77
Mutation Taster		=100/0	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: rs200740143; hg19: chr15-33954552;