NM_001036.6:c.12558C>G

Variant names:

• chr15-33838538-C-G
• rs73372074
• NM_001036.6:c.12558C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001036.6(RYR3):​c.12558C>G​(p.Ser4186Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,862 control chromosomes in the GnomAD database, including 1,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S4186S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.046 (420 hom., cov: 32)
  • Exomes 𝑓: 0.011 (729 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.04
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 15-33838538-C-G is Benign according to our data. Variant chr15-33838538-C-G is described in ClinVar as Benign. ClinVar VariationId is 461853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.12558C>G	p.Ser4186Ser	synonymous_variant	Exon 89 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.12558C>G	p.Ser4186Ser	synonymous_variant	Exon 89 of 104	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6932 AN: 152082 Hom.: 420 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0722

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.0359

GnomAD2 exomes AF: 0.0220 AC: 5482 AN: 249014 AF XY: 0.0223

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.00336

Gnomad OTH exome AF: 0.0190

GnomAD4 exome AF: 0.0112 AC: 16376 AN: 1461662 Hom.: 729 Cov.: 32 AF XY: 0.0125 AC XY: 9076 AN XY: 727106

African (AFR) AF: 0.154 AC: 5151 AN: 33478

American (AMR) AF: 0.0142 AC: 633 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 307 AN: 26134

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39696

South Asian (SAS) AF: 0.0690 AC: 5953 AN: 86252

European-Finnish (FIN) AF: 0.00272 AC: 145 AN: 53400

Middle Eastern (MID) AF: 0.0303 AC: 175 AN: 5768

European-Non Finnish (NFE) AF: 0.00251 AC: 2792 AN: 1111848

Other (OTH) AF: 0.0200 AC: 1207 AN: 60372

GnomAD4 genome AF: 0.0456 AC: 6940 AN: 152200 Hom.: 420 Cov.: 32 AF XY: 0.0454 AC XY: 3376 AN XY: 74408

African (AFR) AF: 0.141 AC: 5842 AN: 41494

American (AMR) AF: 0.0244 AC: 374 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.0718 AC: 346 AN: 4816

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10610

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.00312 AC: 212 AN: 68018

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

Alfa AF: 0.0159 Hom.: 36

Bravo AF: 0.0503

Asia WGS AF: 0.0400 AC: 140 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00516

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.21
DANN	Benign	0.53
PhyloP100		-1.0
PromoterAI		0.013	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73372074; hg19: chr15-34130739; COSMIC: COSV66807610; COSMIC: COSV66807610;