Variant 17-42160050-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_012285.3(KCNH4):c.3044C>T(p.Thr1015Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,370,670 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: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

KCNH4
NM_012285.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.91

Variant links:

Genes affected

KCNH4 (HGNC:6253): (potassium voltage-gated channel subfamily H member 4) 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. The gene is brain-specific, and located in the neocortex and the striatum. It may be involved in cellular excitability of restricted neurons in the central nervous system. [provided by RefSeq, Jul 2008]

KCNH4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13211328).

BS2

High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH4	NM_012285.3 linkuse as main transcript	c.3044C>T	p.Thr1015Met	missense_variant	16/17	ENST00000264661.4	NP_036417.1	Q9UQ05

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH4	ENST00000264661.4 linkuse as main transcript	c.3044C>T	p.Thr1015Met	missense_variant	16/17	1	NM_012285.3	ENSP00000264661.2		Q9UQ05
KCNH4	ENST00000607371.5 linkuse as main transcript	c.3044C>T	p.Thr1015Met	missense_variant	16/17	5		ENSP00000475564.1		Q9UQ05

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000433

AC:

AN:

184640

Hom.:

AF XY:

0.0000103

AC XY:

AN XY:

97558

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000368

Gnomad SAS exome

AF:

0.000122

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000139

AC:

AN:

1370670

Hom.:

Cov.:

AF XY:

0.0000104

AC XY:

AN XY:

671216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000309

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000285

Gnomad4 SAS exome

AF:

0.0000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000282

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000417

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

Mar 28, 2023

The c.3044C>T (p.T1015M) alteration is located in exon 16 (coding exon 16) of the KCNH4 gene. This alteration results from a C to T substitution at nucleotide position 3044, causing the threonine (T) at amino acid position 1015 to be replaced by a methionine (M). 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

0.096

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.58

.;T

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.13

T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

0.81

L;L

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.69

.;N

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.013

D;D

Polyphen

0.99

D;D

Vest4

0.15

MutPred

0.099

Loss of glycosylation at T1015 (P = 0.0645);Loss of glycosylation at T1015 (P = 0.0645);

MVP

0.59

MPC

0.76

ClinPred

0.28

GERP RS

4.9

Varity_R

0.098

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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