14-62950163-T-C

Position:

chr14-62950163-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_139318.5(KCNH5):c.1339A>G(p.Met447Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

KCNH5
NM_139318.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.02

Variant links:

Genes affected

KCNH5 (HGNC:6254): (potassium voltage-gated channel subfamily H member 5) This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

KCNH5 links:

KCNH5 (HGNC:):

KCNH5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNH5. . Gene score misZ 2.509 (greater than the threshold 3.09). Trascript score misZ 3.7308 (greater than threshold 3.09). GenCC has associacion of gene with infantile-onset epilepsy.

BP4

Computational evidence support a benign effect (MetaRNN=0.2903145).

BS2

High AC in GnomAdExome4 at 128 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH5	NM_139318.5 linkuse as main transcript	c.1339A>G	p.Met447Val	missense_variant	7/11	ENST00000322893.12	NP_647479.2	Q8NCM2-1
KCNH5	NM_172375.3 linkuse as main transcript	c.1339A>G	p.Met447Val	missense_variant	7/10		NP_758963.1	Q8NCM2-2
KCNH5	XM_047431275.1 linkuse as main transcript	c.1339A>G	p.Met447Val	missense_variant	7/10		XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNH5	ENST00000322893.12 linkuse as main transcript	c.1339A>G	p.Met447Val	missense_variant	7/11	1	NM_139318.5	ENSP00000321427.7	Q8NCM2-1
KCNH5	ENST00000420622.6 linkuse as main transcript	c.1339A>G	p.Met447Val	missense_variant	7/10	1		ENSP00000395439.2	Q8NCM2-2
KCNH5	ENST00000394964.3 linkuse as main transcript	n.1504A>G		non_coding_transcript_exon_variant	7/7	1
KCNH5	ENST00000394968.2 linkuse as main transcript	c.1165A>G	p.Met389Val	missense_variant	7/11	2		ENSP00000378419.1	Q8NCM2-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152066

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251016

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461674

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.0000998

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74260

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.1339A>G (p.M447V) alteration is located in exon 7 (coding exon 7) of the KCNH5 gene. This alteration results from a A to G substitution at nucleotide position 1339, causing the methionine (M) at amino acid position 447 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 447 of the KCNH5 protein (p.Met447Val). This variant is present in population databases (rs200506671, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of KCNH5-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 461386). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNH5 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.45

T;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

-0.64

N;N;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

1.5

N;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.26

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.54

MutPred

0.51

Gain of catalytic residue at V450 (P = 0);Gain of catalytic residue at V450 (P = 0);.;

MVP

0.57

MPC

0.71

ClinPred

0.12

GERP RS

5.8

Varity_R

0.36

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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