rs1554431444

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The ENST00000262186.10(KCNH2):​c.55A>T​(p.Ile19Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I19S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 27)

Consequence

KCNH2
ENST00000262186.10 missense

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.877
Variant links:
Genes affected
KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in ENST00000262186.10
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH2NM_000238.4 linkuse as main transcriptc.55A>T p.Ile19Phe missense_variant 1/15 ENST00000262186.10 NP_000229.1
KCNH2NM_172056.3 linkuse as main transcriptc.55A>T p.Ile19Phe missense_variant 1/9 NP_742053.1
KCNH2NR_176254.1 linkuse as main transcriptn.463A>T non_coding_transcript_exon_variant 1/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.55A>T p.Ile19Phe missense_variant 1/151 NM_000238.4 ENSP00000262186 P1Q12809-1
KCNH2ENST00000532957.5 linkuse as main transcriptn.278A>T non_coding_transcript_exon_variant 1/92

Frequencies

GnomAD3 genomes
Cov.:
27
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
27

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 26, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 527023). This missense change has been observed in individual(s) with long QT syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 19 of the KCNH2 protein (p.Ile19Phe). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.63
D
Eigen
Uncertain
0.19
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.99
D
MetaRNN
Uncertain
0.54
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.8
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-2.3
N
REVEL
Pathogenic
0.80
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.40
B
Vest4
0.36
MutPred
0.44
Loss of methylation at K21 (P = 0.0946);
MVP
0.86
MPC
1.8
ClinPred
0.97
D
GERP RS
2.1
Varity_R
0.60
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554431444; hg19: chr7-150674947; API