dbSNP rs762889425: KCNH3:p.Arg153Ser (chr12-49542717-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012284.3(KCNH3):c.457C>A(p.Arg153Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,425,774 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. R153C) 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: 2.40

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23014066).

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.457C>A	p.Arg153Ser	missense	Exon 4 of 15	NP_036416.1	Q9ULD8
	KCNH3	NM_001314030.2		c.277C>A	p.Arg93Ser	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.457C>A	p.Arg153Ser	missense	Exon 4 of 15	ENSP00000257981.5	Q9ULD8
KCNH3	ENST00000965158.1		c.223C>A	p.Arg75Ser	missense	Exon 3 of 14	ENSP00000635217.1
KCNH3	ENST00000550434.1	TSL:3	n.186C>A		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1425774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705818

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32770

American (AMR)

AF:

0.00

AC:

AN:

39428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25394

East Asian (EAS)

AF:

0.00

AC:

AN:

37958

South Asian (SAS)

AF:

0.00

AC:

AN:

81214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5258

European-Non Finnish (NFE)

AF:

9.14e-7

AC:

AN:

1094652

Other (OTH)

AF:

0.00

AC:

AN:

58970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.093

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.083

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.61

M_CAP

Benign

0.046

MetaRNN

Benign

0.23

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

0.55

PhyloP100

2.4

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.67

REVEL

Uncertain

0.54

Sift

Benign

0.47

Sift4G

Benign

0.64

Polyphen

0.091

Vest4

0.52

MutPred

0.35

Gain of glycosylation at R153 (P = 0.0112)

MVP

0.90

MPC

1.4

ClinPred

0.54

GERP RS

4.5

Varity_R

0.17

gMVP

0.72

Mutation Taster

=74/26

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

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