rs56229512

Variant names:

• chr1-237591776-A-G
• rs56229512
• NM_001035.3:c.4198A>G
• RYR2 p.Ser1400Gly

Your query was ambiguous. Multiple possible variants found:

• chr1-237591776-A-G
• chr1-237591776-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):​c.4198A>G​(p.Ser1400Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,613,390 control chromosomes in the GnomAD database, including 390 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1400S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (19 hom., cov: 31)
  • Exomes 𝑓: 0.022 (371 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 3.54
• Publications: 7 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: Orphanet, G2P, ClinGen
• 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
• hypertrophic cardiomyopathy

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008523673).
• BP6: Variant 1-237591776-A-G is Benign according to our data. Variant chr1-237591776-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0152 (2310/152266) while in subpopulation NFE AF = 0.0239 (1627/68018). AF 95% confidence interval is 0.023. There are 19 homozygotes in GnomAd4. There are 1093 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2310 AD gene.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.4198A>G	p.Ser1400Gly	missense	Exon 32 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.4198A>G	p.Ser1400Gly	missense	Exon 32 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.4198A>G	p.Ser1400Gly	missense	Exon 32 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.4198A>G		non_coding_transcript_exon	Exon 32 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2310 AN: 152148 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0167 AC: 4155 AN: 248504 AF XY: 0.0173

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.00830

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.000224

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0195

GnomAD4 exome AF: 0.0222 AC: 32424 AN: 1461124 Hom.: 371 Cov.: 30 AF XY: 0.0221 AC XY: 16053 AN XY: 726786

African (AFR) AF: 0.00290 AC: 97 AN: 33476

American (AMR) AF: 0.00848 AC: 379 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 503 AN: 26118

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39648

South Asian (SAS) AF: 0.0131 AC: 1125 AN: 86126

European-Finnish (FIN) AF: 0.0221 AC: 1181 AN: 53392

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.0252 AC: 27956 AN: 1111554

Other (OTH) AF: 0.0189 AC: 1138 AN: 60346

GnomAD4 genome AF: 0.0152 AC: 2310 AN: 152266 Hom.: 19 Cov.: 31 AF XY: 0.0147 AC XY: 1093 AN XY: 74456

African (AFR) AF: 0.00390 AC: 162 AN: 41546

American (AMR) AF: 0.0109 AC: 167 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4826

European-Finnish (FIN) AF: 0.0170 AC: 180 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0239 AC: 1627 AN: 68018

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0211 Hom.: 123

Bravo AF: 0.0139

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0222

EpiControl AF: 0.0222

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	5	not provided (5)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2;C5542154:Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0085	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.31
Sift	Benign	0.12	T
Varity_R		0.090
gMVP		0.39
Mutation Taster		=79/21	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

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

Other links and lift over

dbSNP: rs56229512;

hg19: chr1-237755076;