Genetic Variant KCNH3:p.Gly162Ala (chr12-49542745-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_012284.3(KCNH3):c.485G>C(p.Gly162Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,000 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G162V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

KCNH3
NM_012284.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.95

Publications

0 publications found

Variant links:

Genes affected

KCNH3 (HGNC:6252): (potassium voltage-gated channel subfamily H member 3) The protein encoded by this gene is a voltage-gated potassium channel alpha subunit predominantly expressed in the forebrain. Studies in mice have found that cognitive function increases when this gene is knocked out. In humans, the encoded protein has been shown to be capable of binding glycoprotein 120 of the human immunodeficiency virus type 1 (HIV-1) envelope. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2015]

KCNH3 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KCNH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2705816).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012284.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH3	NM_012284.3	MANE Select	c.485G>C	p.Gly162Ala	missense	Exon 4 of 15	NP_036416.1	Q9ULD8
	KCNH3	NM_001314030.2		c.305G>C	p.Gly102Ala	missense	Exon 4 of 15	NP_001300959.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNH3	ENST00000257981.7	TSL:1 MANE Select	c.485G>C	p.Gly162Ala	missense	Exon 4 of 15	ENSP00000257981.5	Q9ULD8
KCNH3	ENST00000965158.1		c.251G>C	p.Gly84Ala	missense	Exon 3 of 14	ENSP00000635217.1
KCNH3	ENST00000550434.1	TSL:3	n.214G>C		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1437000

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33164

American (AMR)

AF:

0.00

AC:

AN:

40414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25526

East Asian (EAS)

AF:

0.00

AC:

AN:

38724

South Asian (SAS)

AF:

0.0000122

AC:

AN:

82258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50986

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100776

Other (OTH)

AF:

0.00

AC:

AN:

59458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

M_CAP

Benign

0.084

MetaRNN

Benign

0.27

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

1.9

PhyloP100

4.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.46

Sift

Benign

0.21

Sift4G

Benign

0.24

Polyphen

0.63

Vest4

0.23

MutPred

0.26

Gain of helix (P = 0.0199)

MVP

0.93

MPC

1.5

ClinPred

0.65

GERP RS

3.5

Varity_R

0.18

gMVP

0.65

Mutation Taster

=44/56

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over