1-237591776-A-T

Variant names:

• chr1-237591776-A-T
• NM_001035.3:c.4198A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001035.3(RYR2):​c.4198A>T​(p.Ser1400Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S1400G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30914053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.4198A>T	p.Ser1400Cys	missense_variant	Exon 32 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.4198A>T	p.Ser1400Cys	missense_variant	Exon 32 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.4198A>T		non_coding_transcript_exon_variant	Exon 32 of 104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.4198A>T	p.Ser1400Cys	missense_variant	Exon 32 of 106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.4198A>T	p.Ser1400Cys	missense_variant	Exon 32 of 105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461358 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726926

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Uncertain	0.58	D;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.3	N;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0080	D;.
Polyphen		0.14	B;.
Vest4		0.65
MutPred		0.23		Loss of disorder (P = 0.0128);.;
MVP		0.78
MPC		0.35
ClinPred		0.75	D
GERP RS		3.2
Varity_R		0.12
gMVP		0.48

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-237755076;