14-62950404-T-C

Position:

chr14-62950404-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_139318.5(KCNH5):c.1098A>G(p.Ile366Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,613,944 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I366V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

KCNH5
NM_139318.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.956

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 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=0.040032953).

BP6

Variant 14-62950404-T-C is Benign according to our data. Variant chr14-62950404-T-C is described in ClinVar as [Benign]. Clinvar id is 416115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-62950404-T-C is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 123 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNH5	NM_139318.5 linkuse as main transcript	c.1098A>G	p.Ile366Met	missense_variant	7/11	ENST00000322893.12
KCNH5	NM_172375.3 linkuse as main transcript	c.1098A>G	p.Ile366Met	missense_variant	7/10
KCNH5	XM_047431275.1 linkuse as main transcript	c.1098A>G	p.Ile366Met	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH5	ENST00000322893.12 linkuse as main transcript	c.1098A>G	p.Ile366Met	missense_variant	7/11	1	NM_139318.5	P1	Q8NCM2-1
KCNH5	ENST00000420622.6 linkuse as main transcript	c.1098A>G	p.Ile366Met	missense_variant	7/10	1			Q8NCM2-2
KCNH5	ENST00000394964.3 linkuse as main transcript	n.1263A>G		non_coding_transcript_exon_variant	7/7	1
KCNH5	ENST00000394968.2 linkuse as main transcript	c.924A>G	p.Ile308Met	missense_variant	7/11	2			Q8NCM2-3

Frequencies

GnomAD3 genomes

AF:

0.000809

AC:

123

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000787

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00114

AC:

285

AN:

250870

Hom.:

AF XY:

0.00106

AC XY:

144

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00108

AC:

1586

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

782

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00228

Gnomad4 ASJ exome

AF:

0.00574

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00107

Gnomad4 OTH exome

AF:

0.00177

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152142

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000786

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00138

Hom.:

Bravo

AF:

0.000929

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00105

AC:

127

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

KCNH5-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.82

D;.;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.040

T;T;T

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

1.5

L;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.5

D;D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.028

D;D;D

Sift4G

Uncertain

0.049

D;T;T

Polyphen

0.85

P;B;P

Vest4

0.86

MVP

0.94

MPC

1.8

ClinPred

0.058

GERP RS

-6.6

Varity_R

0.45

gMVP

0.70

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