chr15-33755060-C-T

Variant names:

• chr15-33755060-C-T
• rs74437672
• NM_001036.6:c.8400-5C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001036.6(RYR3):​c.8400-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,576,086 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (125 hom.)
• Consequence: RYR3 NM_001036.6 splice_region, intron
• Scores: Splicing: ADA: 0.00005025
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0290
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-33755060-C-T is Benign according to our data. Variant chr15-33755060-C-T is described in ClinVar as Benign. ClinVar VariationId is 461966.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0781 is higher than 0.05.

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.8400-5C>T		splice_region intron	N/A	NP_001027.3
	RYR3	NM_001243996.4		c.8400-5C>T		splice_region intron	N/A	NP_001230925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.8400-5C>T		splice_region intron	N/A	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.8397-5C>T		splice_region intron	N/A	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.8400-5C>T		splice_region intron	N/A	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 552 AN: 152116 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0845

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00788 AC: 1927 AN: 244682 AF XY: 0.00710

Gnomad AFR exome AF: 0.000595

Gnomad AMR exome AF: 0.00813

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.0897

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00254 AC: 3618 AN: 1423852 Hom.: 125 Cov.: 26 AF XY: 0.00240 AC XY: 1702 AN XY: 710486

African (AFR) AF: 0.000581 AC: 19 AN: 32724

American (AMR) AF: 0.00698 AC: 310 AN: 44384

Ashkenazi Jewish (ASJ) AF: 0.000387 AC: 10 AN: 25808

East Asian (EAS) AF: 0.0688 AC: 2712 AN: 39428

South Asian (SAS) AF: 0.000768 AC: 65 AN: 84592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5696

European-Non Finnish (NFE) AF: 0.0000306 AC: 33 AN: 1078730

Other (OTH) AF: 0.00791 AC: 468 AN: 59176

GnomAD4 genome AF: 0.00364 AC: 554 AN: 152234 Hom.: 20 Cov.: 32 AF XY: 0.00404 AC XY: 301 AN XY: 74434

African (AFR) AF: 0.00116 AC: 48 AN: 41544

American (AMR) AF: 0.00281 AC: 43 AN: 15290

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

East Asian (EAS) AF: 0.0847 AC: 438 AN: 5174

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68016

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00135 Hom.: 2

Bravo AF: 0.00445

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR3-related disorder Benign:1

Jun 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.2
DANN	Benign	0.43
PhyloP100		0.029
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.0
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: rs74437672; hg19: chr15-34047261;