Variant chr17-63530241-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001278919.2(KCNH6):c.458T>A(p.Phe153Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

KCNH6
NM_001278919.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01

Variant links:

Genes affected

KCNH6 (HGNC:18862): (potassium voltage-gated channel subfamily H member 6) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit. Alternative splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Jul 2013]

KCNH6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12816626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH6	NM_001278919.2 linkuse as main transcript	c.458T>A	p.Phe153Tyr	missense_variant	3/13	ENST00000314672.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH6	ENST00000314672.10 linkuse as main transcript	c.458T>A	p.Phe153Tyr	missense_variant	3/13	2	NM_001278919.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152166

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251162

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135782

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:

0.000231

Gnomad NFE exome

AF:

0.000379

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000602

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

727166

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:

0.000393

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74336

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:

0.000188

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000455

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000354

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.458T>A (p.F153Y) alteration is located in exon 3 (coding exon 3) of the KCNH6 gene. This alteration results from a T to A substitution at nucleotide position 458, causing the phenylalanine (F) at amino acid position 153 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.067

.;.;.;.;T

Eigen

Benign

-0.094

Eigen_PC

Benign

0.011

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.71

T;.;T;T;T

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

0.97

L;L;L;.;L

MutationTaster

Benign

0.92

N;N;N;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.26

N;.;.;N;.

REVEL

Uncertain

0.39

Sift

Benign

0.85

T;.;.;T;.

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.96

D;D;B;.;P

Vest4

0.29

MVP

0.77

MPC

0.25

ClinPred

0.072

GERP RS

4.6

Varity_R

0.096

gMVP

0.30

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