chr1-237614040-T-C

Variant names:

• chr1-237614040-T-C
• rs794728739
• NM_001035.3:c.4912T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001035.3(RYR2):​c.4912T>C​(p.Ser1638Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,458,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S1638T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense, splice_region
• Scores: Splicing: ADA: 0.1981
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16
• 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: 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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.4912T>C	p.Ser1638Pro	missense_variant, splice_region_variant	Exon 37 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.4912T>C	p.Ser1638Pro	missense_variant, splice_region_variant	Exon 37 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.4912T>C	p.Ser1638Pro	missense_variant, splice_region_variant	Exon 37 of 106			ENSP00000499393.2
RYR2	ENST00000609119.2	n.4912T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 37 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458474 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724868

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109328

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.7	L;.
PhyloP100		6.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0040	D;.
Polyphen		0.61	P;.
Vest4		0.77
MutPred		0.49		Loss of stability (P = 0.0366);.;
MVP		0.89
MPC		0.51
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.40
gMVP		0.65
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.20
dbscSNV1_RF	Benign	0.42
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: rs794728739; hg19: chr1-237777340;