NM_001035.3:c.13291_13293delGAAinsAAG

Variant names:

• chr1-237785999-GAA-AAG
• NM_001035.3:c.13291_13293delGAAinsAAG
• RYR2 p.Glu4431Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB2_Supporting

The NM_001035.3(RYR2):c.13291_13293delGAAinsAAG (p.Glu4431Lys) variant causes a missense change. The gene RYR2 is a tumor suppressor gene (CancerMine: 2 TSG citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E4431= (synonymous): Benign/Likely_benign (ClinVar VariationId 496090, 2 stars); p.E4431K: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 165128) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.55
• Publications: 0 publications found

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

RYR2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Ambry Genetics, Laboratory for Molecular Medicine
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: G2P, ClinGen

ENSG00000296715 (HGNC:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	B2Does not fit gene mode of action		Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context); Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RYR2 NM_001035.3	MANE Select	c.13291_13293delGAAinsAAG p.Glu4431Lys	missense	N/A	Prot: NP_001026.2 UniProt:

RYR2 NM_001035.3

MANE Select

HGVSc / HGVSpc.13291_13293delGAAinsAAGp.Glu4431Lys

Exon rankN/A

missense

Prot: NP_001026.2UniProt: Q92736-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RYR2 ENST00000366574.7	TSL:1MANE Select	c.13291_13293delGAAinsAAG p.Glu4431Lys	missense	N/A	Prot: ENSP00000355533.2 UniProt:
	RYR2 ENST00000661330.2		c.13309_13311delGAAinsAAG p.Glu4437Lys	missense	N/A	Prot: ENSP00000499393.2 UniProt:
	RYR2 ENST00000609119.2	TSL:5	n.*4383_*4385delGAAinsAAG	3_prime_UTR	Exon 90 of 104	Prot: ENSP00000499659.2 UniProt:

RYR2 ENST00000366574.7

TSL:1MANE Select

HGVSc / HGVSpc.13291_13293delGAAinsAAGp.Glu4431Lys

Exon rankN/A

missense

Prot: ENSP00000355533.2UniProt: Q92736-1

RYR2 ENST00000661330.2

HGVSc / HGVSpc.13309_13311delGAAinsAAGp.Glu4437Lys

Exon rankN/A

missense

Prot: ENSP00000499393.2UniProt: A0A590UJF6

RYR2 ENST00000609119.2

TSL:5

HGVSc / HGVSpn.*4383_*4385delGAAinsAAG

Exon rankExon 90 of 104

3_prime_UTR

Prot: ENSP00000499659.2UniProt: A0A590UK06

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	4.5

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr1-237949299;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar