7-150952720-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_000238.4(KCNH2):​c.1262C>A​(p.Thr421Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T421M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KCNH2
NM_000238.4 missense

Scores

13
4
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.81
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 Pathogenic. Variant got 10 ACMG points.

PM1
In a transmembrane_region Helical; Name=Segment S1 (size 20) in uniprot entity KCNH2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000238.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-150952720-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.928
PP5
Variant 7-150952720-G-T is Pathogenic according to our data. Variant chr7-150952720-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 200331.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNH2NM_000238.4 linkc.1262C>A p.Thr421Lys missense_variant Exon 6 of 15 ENST00000262186.10 NP_000229.1 Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkc.1262C>A p.Thr421Lys missense_variant Exon 6 of 15 1 NM_000238.4 ENSP00000262186.5 Q12809-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Pathogenic:1
Mar 31, 2013
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Thr421Lys (ACG>AAG): c.1262 C>A in exon 6 of the KCNH2 (aka HERG) gene (NM_000238.2)While the Thr421Lys mutation in the KCNH2 gene has not been reported to our knowledge, a mutation affecting this same codon, Thr421Met, has been reported in association with LQTS (Tester D et al., 2005). Additionally, mutations in nearby residues (Leu413Pro, Tyr420Cys, Ala422Thr) have been reported in association with LQTS, further supporting the functional importance of this codon and this region of the protein. Thr421Lys results in a semi-conservative amino acid substitution of a neutral, polar Threonine with a positively charged Lysine at a position that is conserved across species. In silico analysis predicts Thr421Lys is probably damaging to the protein structure/function. Furthermore, Thr421Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, Thr421Lys in the KCNH2 gene is interpreted as a likely disease-causing mutation. The variant is found in LQT panel(s). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.99
.;D;D
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.93
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.4
.;M;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-5.7
D;D;N
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;T
Sift4G
Benign
0.062
T;T;T
Polyphen
0.91
P;D;.
Vest4
0.94
MutPred
0.71
.;Gain of ubiquitination at T421 (P = 0.0267);.;
MVP
1.0
MPC
2.4
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.97
gMVP
0.99

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

LitVar

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

Other links and lift over

dbSNP: rs199472894; hg19: chr7-150649808; API