rs1554425151

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_172056.3(KCNH2):​c.2401A>G​(p.Met801Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. M801I) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 28)

Consequence

KCNH2
NM_172056.3 missense

Scores

4
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.69
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a binding_site (size 100) in uniprot entity KCNH2_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_172056.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-150950163-C-A is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNH2. . Gene score misZ 3.3724 (greater than the threshold 3.09). Trascript score misZ 3.4405 (greater than threshold 3.09). GenCC has associacion of gene with Brugada syndrome, long QT syndrome, short QT syndrome, short QT syndrome type 1, long QT syndrome 2.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH2NM_000238.4 linkuse as main transcriptc.2398+3A>G splice_region_variant, intron_variant ENST00000262186.10 NP_000229.1 Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.2398+3A>G splice_region_variant, intron_variant 1 NM_000238.4 ENSP00000262186.5 Q12809-1

Frequencies

GnomAD3 genomes
Cov.:
28
GnomAD4 exome
Cov.:
23
GnomAD4 genome
Cov.:
28

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Long QT syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 04, 2021In 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with long QT syndrome (LQTS) (PMID: 16414944). ClinVar contains an entry for this variant (Variation ID: 523701). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 9 of the KCNH2 gene. It does not directly change the encoded amino acid sequence of the KCNH2 protein. It affects a nucleotide within the consensus splice site of the intron. -
Uncertain significance, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteJun 12, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.092
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.26
T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.14
FATHMM_MKL
Benign
0.57
D
LIST_S2
Benign
0.69
T
M_CAP
Benign
0.062
D
MetaRNN
Benign
0.18
T
MetaSVM
Uncertain
0.11
D
REVEL
Uncertain
0.33
Sift4G
Uncertain
0.055
T
Vest4
0.21
MVP
0.26
ClinPred
0.71
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.79
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.79
Position offset: 3

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: rs1554425151; hg19: chr7-150647253; API