rs571985775

Variant names:

• chr1-237785999-G-A
• rs571985775
• NM_001035.3:c.13291G>A
• RYR2 p.Glu4431Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP6

The ENST00000741291.1(ENSG00000296715):n.140-1323C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: ENST00000741291.1 is not a MANE Select or MANE Plus Clinical transcript for ENSG00000296715; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.000558 (AC=889) in the gnomAD database across 1,591,854 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000704. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: ENSG00000296715 ENST00000741291.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:5
• Conservation: PhyloP100: 4.55
• Publications: 11 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000704 — borderline rare for unknown gene (threshold 0.001) — PM2 supporting.
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000741291.1. 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.13291G>A	p.Glu4431Lys	missense	Exon 91 of 105	NP_001026.2	Q92736-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.13291G>A	p.Glu4431Lys	missense	Exon 91 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.13309G>A	p.Glu4437Lys	missense	Exon 92 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*4383G>A		3_prime_UTR	Exon 90 of 104	ENSP00000499659.2	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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000269	AC:41	Hom:0	AN:152156	Cov:32
GnomAD2 exomes	AF: 0.000246	AC:52	Hom:	AN:211502	Cov:
GnomAD4 exome	AF: 0.000589	AC:848	Hom:0	AN:1439580	Cov:29
GnomAD4 genome	AF: 0.000269	AC:41	Hom:0	AN:152274	Cov:32
TOPMed (Bravo)	AF: 0.000280	AC:74	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000397	AC:33	Hom:0	AN:83168	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
UK10K	AF: 0.000926	AC:7	Hom:	AN:7562	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000520 *	5	9622	0.000192 *	2	10428
BipEx(Bipolar disorder (including schizoaffective))	0.000528	15	28420	0.000381	11	28844

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	-	not provided (6)
-	1	2	Catecholaminergic polymorphic ventricular tachycardia 1 (3)
-	2	-	Arrhythmogenic right ventricular dysplasia 2 (2)
-	1	1	not specified (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	1	-	Left ventricular noncompaction (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	0.0089	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.16
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.94	D
FuncVEP CTI	Benign	0.0025
GPN-Star LLR	N/A	-7.8
GPN-Star score	N/A	7.8
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.029	T
Mutation Taster	N/A	87/13	polymorphism
MutationAssessor	Benign	1.7	L
PhyloP100	Uncertain	4.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.53
Sift	Benign	0.81	T
Varity_R	N/A	0.22
VESM-3B	Benign	-4.0

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2
Splicevardb	N/A	0.0

Showing 3 of 3 scores

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.

Other links and lift over

dbSNP: rs571985775;

hg19: chr1-237949299;

COSMIC: COSV63675863;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar