NM_000238.4:c.775G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BS2

The NM_000238.4(KCNH2):​c.775G>A​(p.Asp259Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,364,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D259D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

2
9
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5O:1

Conservation

PhyloP100: 2.17

Publications

7 publications found
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]
KCNH2 Gene-Disease associations (from GenCC):
  • long QT syndrome
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • long QT syndrome 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • short QT syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • short QT syndrome type 1
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • Brugada syndrome
    Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
BS2
High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNH2NM_000238.4 linkc.775G>A p.Asp259Asn missense_variant Exon 4 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.775G>A p.Asp259Asn missense_variant Exon 4 of 15 1 NM_000238.4 ENSP00000262186.5 Q12809-1

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151840
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000280
AC:
1
AN:
35660
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000107
AC:
13
AN:
1212186
Hom.:
0
Cov.:
31
AF XY:
0.00000847
AC XY:
5
AN XY:
590110
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
24436
American (AMR)
AF:
0.00
AC:
0
AN:
15246
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
18738
East Asian (EAS)
AF:
0.0000376
AC:
1
AN:
26576
South Asian (SAS)
AF:
0.0000388
AC:
2
AN:
51584
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
29554
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3492
European-Non Finnish (NFE)
AF:
0.00000806
AC:
8
AN:
992976
Other (OTH)
AF:
0.0000403
AC:
2
AN:
49584
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151840
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74172
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41398
American (AMR)
AF:
0.00
AC:
0
AN:
15232
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10488
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67928
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000268
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jul 11, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Identified in patients with LQTS in published literature (PMID: 32383558, 19716085); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest that the p.(D259N) variant does not significantly affect KCNH2 function (PMID: 34002542, 38219013); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19716085, 34002542, 32383558, 35932045, LiuY2024[Article], 38219013) -

May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

KCNH2: PM2, PP3 -

Long QT syndrome Uncertain:2
Dec 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 259 of the KCNH2 protein (p.Asp259Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 19716085, 32383558). ClinVar contains an entry for this variant (Variation ID: 67527). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 34002542). In 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. -

Sep 12, 2023
Clinical Genomics Laboratory, Washington University in St. Louis
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The KCNH2 c.775G>A (p.Asp259Asn) variant was identified in a heterozygous state. It has been reported in two individuals affected with long QT syndrome and one case of Sudden Unexpected Death in Epilepsy (SUDEP) (Westphal DS et al., PMID: 32383558; Kapplinger JD et al., PMID: 19716085; Soh MS et al.; PMID: 34002542). This variant has been reported the ClinVar database as a variant of uncertain significance by three submitters (ClinVar ID: 67527). It is only observed on 2/66574 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors are uncertain as to the impact of this variant on KCNH2 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as being of uncertain significance at this time. -

Cardiovascular phenotype Uncertain:1
Feb 22, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.775G>A (p.D259N) alteration is located in exon 4 (coding exon 4) of the KCNH2 gene. This alteration results from a G to A substitution at nucleotide position 775, causing the aspartic acid (D) at amino acid position 259 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital long QT syndrome Other:1
-
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
CardioboostArm
Benign
0.00016
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.47
T;T
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.53
FATHMM_MKL
Benign
0.20
N
LIST_S2
Benign
0.78
T;T
M_CAP
Pathogenic
0.91
D
MetaRNN
Uncertain
0.45
T;T
MetaSVM
Uncertain
0.60
D
MutationAssessor
Benign
0.81
L;.
PhyloP100
2.2
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-1.4
N;.
REVEL
Uncertain
0.49
Sift
Uncertain
0.0040
D;.
Sift4G
Uncertain
0.052
T;T
Polyphen
0.98
D;.
Vest4
0.30
MutPred
0.75
Gain of MoRF binding (P = 0.0365);.;
MVP
0.87
MPC
0.98
ClinPred
0.12
T
GERP RS
3.6
Varity_R
0.15
gMVP
0.50
Mutation Taster
=6/94
disease causing

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

Other links and lift over

dbSNP: rs199472876; hg19: chr7-150655288; API