Variant rs199472876 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

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 (★★).

Frequency

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

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 2.17

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 links:

KCNH2 (HGNC:):

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 13 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.775G>A	p.Asp259Asn	missense_variant	4/15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.775G>A	p.Asp259Asn	missense_variant	4/15	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000532957.5 linkuse as main transcript	n.998G>A		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.1608G>A		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151840

Hom.:

Cov.:

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

GnomAD4 exome

AF:

0.0000107

AC:

AN:

1212186

Hom.:

Cov.:

AF XY:

0.00000847

AC XY:

AN XY:

590110

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000376

Gnomad4 SAS exome

AF:

0.0000388

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000806

Gnomad4 OTH exome

AF:

0.0000403

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151840

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000268

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2022	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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Sep 12, 2023	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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2024

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) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2022

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

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

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

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.91

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

0.81

L;.

PrimateAI

Pathogenic

0.91

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

GERP RS

3.6

Varity_R

0.15

gMVP

0.50

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over