NM_001036.6:c.11289C>T

Variant names:

• chr15-33827242-C-T
• rs138744371
• NM_001036.6:c.11289C>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.11289C>T​(p.Thr3763Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00643 in 1,552,718 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (41 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.08
• 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: 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=-0.63).
• BP6: Variant 15-33827242-C-T is Benign according to our data. Variant chr15-33827242-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 461839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 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.11289C>T	p.Thr3763Thr	synonymous	Exon 85 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.11274C>T	p.Thr3758Thr	synonymous	Exon 84 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.11289C>T	p.Thr3763Thr	synonymous	Exon 85 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.11286C>T	p.Thr3762Thr	synonymous	Exon 85 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.11274C>T	p.Thr3758Thr	synonymous	Exon 84 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 704 AN: 152190 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00725

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00420 AC: 662 AN: 157580 AF XY: 0.00417

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.000232

Gnomad EAS exome AF: 0.000998

Gnomad FIN exome AF: 0.00746

Gnomad NFE exome AF: 0.00707

Gnomad OTH exome AF: 0.00431

GnomAD4 exome AF: 0.00663 AC: 9278 AN: 1400410 Hom.: 41 Cov.: 31 AF XY: 0.00653 AC XY: 4512 AN XY: 690808

African (AFR) AF: 0.00117 AC: 37 AN: 31612

American (AMR) AF: 0.00190 AC: 68 AN: 35786

Ashkenazi Jewish (ASJ) AF: 0.000198 AC: 5 AN: 25194

East Asian (EAS) AF: 0.000699 AC: 25 AN: 35774

South Asian (SAS) AF: 0.000631 AC: 50 AN: 79254

European-Finnish (FIN) AF: 0.00626 AC: 309 AN: 49384

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5702

European-Non Finnish (NFE) AF: 0.00790 AC: 8524 AN: 1079624

Other (OTH) AF: 0.00444 AC: 258 AN: 58080

GnomAD4 genome AF: 0.00462 AC: 704 AN: 152308 Hom.: 4 Cov.: 32 AF XY: 0.00430 AC XY: 320 AN XY: 74480

African (AFR) AF: 0.00101 AC: 42 AN: 41574

American (AMR) AF: 0.00320 AC: 49 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00584 AC: 62 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00725 AC: 493 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00546 Hom.: 1

Bravo AF: 0.00431

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR3: BP4, BP7, BS2

Epileptic encephalopathy Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.64
DANN	Benign	0.56
PhyloP100		-1.1
Mutation Taster		=89/11	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: rs138744371; hg19: chr15-34119443;