rs187371252

Variant names:

• chr15-33663602-A-G
• rs187371252
• NM_001036.6:c.5484A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001036.6(RYR3):​c.5484A>G​(p.Ala1828Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,613,652 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0710
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-33663602-A-G is Benign according to our data. Variant chr15-33663602-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 461929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.071 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.5484A>G	p.Ala1828Ala	synonymous	Exon 36 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.5484A>G	p.Ala1828Ala	synonymous	Exon 36 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.5484A>G	p.Ala1828Ala	synonymous	Exon 36 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.5484A>G	p.Ala1828Ala	synonymous	Exon 36 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.5484A>G	p.Ala1828Ala	synonymous	Exon 36 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00132 AC: 327 AN: 248620 AF XY: 0.00125

Gnomad AFR exome AF: 0.000455

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000836

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00190 AC: 2782 AN: 1461380 Hom.: 5 Cov.: 31 AF XY: 0.00180 AC XY: 1310 AN XY: 726894

African (AFR) AF: 0.000388 AC: 13 AN: 33476

American (AMR) AF: 0.000224 AC: 10 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86078

European-Finnish (FIN) AF: 0.00103 AC: 55 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00231 AC: 2566 AN: 1111798

Other (OTH) AF: 0.00182 AC: 110 AN: 60364

GnomAD4 genome AF: 0.00120 AC: 182 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74464

African (AFR) AF: 0.000433 AC: 18 AN: 41568

American (AMR) AF: 0.000327 AC: 5 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00218 AC: 148 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00106

EpiCase AF: 0.00240

EpiControl AF: 0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Apr 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Sep 01, 2024

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	-0.43
CADD	Benign	6.0
DANN	Benign	0.71
PhyloP100		0.071
Mutation Taster		=74/26	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: rs187371252; hg19: chr15-33955803;