chr1-237441448-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001035.3(RYR2):​c.1135G>T​(p.Val379Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,445,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V379M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.3493129).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.1135G>T	p.Val379Leu	missense	Exon 13 of 105	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.1135G>T	p.Val379Leu	missense	Exon 13 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.1135G>T	p.Val379Leu	missense	Exon 13 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.1135G>T		non_coding_transcript_exon	Exon 13 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000413 AC: 1 AN: 242258 AF XY: 0.00000761

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445942 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718364

African (AFR) AF: 0.00 AC: 0 AN: 33076

American (AMR) AF: 0.00 AC: 0 AN: 43866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25606

East Asian (EAS) AF: 0.00 AC: 0 AN: 39400

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82914

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102886

Other (OTH) AF: 0.00 AC: 0 AN: 59706

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.019
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift	Benign	0.041	D
Polyphen		0.0	B
Vest4		0.34
MutPred		0.46		Loss of methylation at K380 (P = 0.0355)
MVP		0.56
MPC		0.36
ClinPred		0.62	D
GERP RS		4.4
Varity_R		0.14
gMVP		0.30
Mutation Taster		=60/40	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;