Genetic Variant NM_012284.3:c.484G>C (chr12-49542744-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.484G>C(p.Gly162Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,436,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G162A) 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

Not reported in ClinVar

Conservation

PhyloP100: 4.90

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:

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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=0.32379067).

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.484G>C	p.Gly162Arg	missense	Exon 4 of 15	NP_036416.1	Q9ULD8
	KCNH3	NM_001314030.2		c.304G>C	p.Gly102Arg	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.484G>C	p.Gly162Arg	missense	Exon 4 of 15	ENSP00000257981.5	Q9ULD8
KCNH3	ENST00000965158.1		c.250G>C	p.Gly84Arg	missense	Exon 3 of 14	ENSP00000635217.1
KCNH3	ENST00000550434.1	TSL:3	n.213G>C		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1436920

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33156

American (AMR)

AF:

0.00

AC:

AN:

40412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25528

East Asian (EAS)

AF:

0.00

AC:

AN:

38712

South Asian (SAS)

AF:

0.00

AC:

AN:

82246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50990

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1100732

Other (OTH)

AF:

0.00

AC:

AN:

59450

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

M_CAP

Benign

0.056

MetaRNN

Benign

0.32

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

1.2

PhyloP100

4.9

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.51

Sift

Benign

0.22

Sift4G

Benign

0.25

Polyphen

0.89

Vest4

0.43

MutPred

0.30

Gain of methylation at G162 (P = 0.0199)

MVP

0.86

MPC

1.4

ClinPred

0.82

GERP RS

4.5

Varity_R

0.20

gMVP

0.74

Mutation Taster

=58/42

polymorphism

(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

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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