Variant rs794728401 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The ENST00000262186.10(KCNH2):c.3002G>T(p.Trp1001Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,428,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1001C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNH2
ENST00000262186.10 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.61

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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, 10 uncertain in ENST00000262186.10

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.3002G>T	p.Trp1001Leu	missense_variant	13/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.3002G>T	p.Trp1001Leu	missense_variant	13/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.1982G>T	p.Trp661Leu	missense_variant	9/11	1		ENSP00000328531		Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.3835G>T		non_coding_transcript_exon_variant	11/13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1428284

Hom.:

Cov.:

AF XY:

0.00000283

AC XY:

AN XY:

707314

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000274

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

.;D

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.9

.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Pathogenic

0.88

Sift

Benign

0.039

D;T

Sift4G

Benign

0.23

T;T

Polyphen

0.79

P;P

Vest4

0.64

MutPred

0.74

.;Gain of disorder (P = 0.0202);

MVP

0.76

MPC

0.87

ClinPred

0.99

GERP RS

4.9

Varity_R

0.75

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over