rs1273768005

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_012284.3(KCNH3):c.475C>G(p.Arg159Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,433,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KCNH3
NM_012284.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.38

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04903835).

BP6

Variant 12-49542735-C-G is Benign according to our data. Variant chr12-49542735-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3532360.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH3	NM_012284.3 link	c.475C>G	p.Arg159Gly	missense_variant	Exon 4 of 15	ENST00000257981.7	NP_036416.1	Q9ULD8
KCNH3	NM_001314030.2 link	c.295C>G	p.Arg99Gly	missense_variant	Exon 4 of 15		NP_001300959.1	Q9ULD8
KCNH3	XM_011538085.3 link	c.475C>G	p.Arg159Gly	missense_variant	Exon 4 of 15		XP_011536387.1
KCNH3	XM_047428613.1 link	c.475C>G	p.Arg159Gly	missense_variant	Exon 4 of 10		XP_047284569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNH3	ENST00000257981.7 link	c.475C>G	p.Arg159Gly	missense_variant	Exon 4 of 15	1	NM_012284.3	ENSP00000257981.5	Q9ULD8
KCNH3	ENST00000550434.1 link	n.204C>G		non_coding_transcript_exon_variant	Exon 3 of 5	3
KCNH3	ENST00000649994.1 link	n.*85C>G		non_coding_transcript_exon_variant	Exon 5 of 16			ENSP00000497890.1	A0A3B3ITH0
KCNH3	ENST00000649994.1 link	n.*85C>G		3_prime_UTR_variant	Exon 5 of 16			ENSP00000497890.1	A0A3B3ITH0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000100

AC:

AN:

199022

Hom.:

AF XY:

0.00000933

AC XY:

AN XY:

107204

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000232

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1433340

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710154

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:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 19, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.041

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.069

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.61

M_CAP

Benign

0.019

MetaRNN

Benign

0.049

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

-0.49

PrimateAI

Benign

0.45

PROVEAN

Benign

0.80

REVEL

Benign

0.25

Sift

Benign

0.50

Sift4G

Benign

0.43

Polyphen

0.0

Vest4

0.14

MutPred

0.35

Loss of methylation at R159 (P = 0.0101);

MVP

0.31

MPC

1.4

ClinPred

0.025

GERP RS

1.6

Varity_R

0.066

gMVP

0.71

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