1-237441448-G-A

Variant names:

• chr1-237441448-G-A
• rs199693714
• NM_001035.3:c.1135G>A

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.1135G>A​(p.Val379Met) variant causes a missense change. The variant allele was found at a frequency of 0.000194 in 1,598,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V379G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.14
• Publications: 4 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: Laboratory for Molecular Medicine, Ambry Genetics
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet
• 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 hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.019839793).
• BP6: Variant 1-237441448-G-A is Benign according to our data. Variant chr1-237441448-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 43708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000992 (151/152262) while in subpopulation AFR AF = 0.00332 (138/41560). AF 95% confidence interval is 0.00287. There are 0 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 151 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.1135G>A	p.Val379Met	missense	Exon 13 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.1135G>A	p.Val379Met	missense	Exon 13 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.1135G>A	p.Val379Met	missense	Exon 13 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.1135G>A		non_coding_transcript_exon	Exon 13 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000215 AC: 52 AN: 242258 AF XY: 0.000129

Gnomad AFR exome AF: 0.00305

Gnomad AMR exome AF: 0.000152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 159 AN: 1445942 Hom.: 0 Cov.: 31 AF XY: 0.0000891 AC XY: 64 AN XY: 718364

African (AFR) AF: 0.00351 AC: 116 AN: 33076

American (AMR) AF: 0.000137 AC: 6 AN: 43866

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25606

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39400

South Asian (SAS) AF: 0.0000362 AC: 3 AN: 82914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52796

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5692

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1102886

Other (OTH) AF: 0.000268 AC: 16 AN: 59706

GnomAD4 genome AF: 0.000992 AC: 151 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74438

African (AFR) AF: 0.00332 AC: 138 AN: 41560

American (AMR) AF: 0.000719 AC: 11 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.00120

ESP6500AA AF: 0.00215 AC: 8

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000257 AC: 31

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.020	D
Polyphen		0.70	P
Vest4		0.28
MVP		0.62
MPC		0.54
ClinPred		0.025	T
GERP RS		4.4
Varity_R		0.10
gMVP		0.27
Mutation Taster		=64/36	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: rs199693714; hg19: chr1-237604748; COSMIC: COSV63721844;