12-49542732-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_012284.3(KCNH3):​c.472G>A​(p.Ala158Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 1,432,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

KCNH3
NM_012284.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62
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]

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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=0.12321925).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH3NM_012284.3 linkc.472G>A p.Ala158Thr missense_variant 4/15 ENST00000257981.7 NP_036416.1 Q9ULD8
KCNH3NM_001314030.2 linkc.292G>A p.Ala98Thr missense_variant 4/15 NP_001300959.1 Q9ULD8
KCNH3XM_011538085.3 linkc.472G>A p.Ala158Thr missense_variant 4/15 XP_011536387.1
KCNH3XM_047428613.1 linkc.472G>A p.Ala158Thr missense_variant 4/10 XP_047284569.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH3ENST00000257981.7 linkc.472G>A p.Ala158Thr missense_variant 4/151 NM_012284.3 ENSP00000257981.5 Q9ULD8
KCNH3ENST00000550434.1 linkn.201G>A non_coding_transcript_exon_variant 3/53
KCNH3ENST00000649994.1 linkn.*82G>A non_coding_transcript_exon_variant 5/16 ENSP00000497890.1 A0A3B3ITH0
KCNH3ENST00000649994.1 linkn.*82G>A 3_prime_UTR_variant 5/16 ENSP00000497890.1 A0A3B3ITH0

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000349
AC:
5
AN:
1432270
Hom.:
0
Cov.:
31
AF XY:
0.00000564
AC XY:
4
AN XY:
709522
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000250
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000489
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

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 submitterclinical testingAmbry GeneticsJan 03, 2024The c.472G>A (p.A158T) alteration is located in exon 4 (coding exon 4) of the KCNH3 gene. This alteration results from a G to A substitution at nucleotide position 472, causing the alanine (A) at amino acid position 158 to be replaced by a threonine (T). 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
0.074
BayesDel_addAF
Benign
0.0047
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.078
T
Eigen
Benign
-0.64
Eigen_PC
Benign
-0.48
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.60
T
M_CAP
Uncertain
0.090
D
MetaRNN
Benign
0.12
T
MetaSVM
Uncertain
0.45
D
MutationAssessor
Benign
0.0
N
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
0.080
N
REVEL
Benign
0.26
Sift
Benign
0.20
T
Sift4G
Benign
0.67
T
Polyphen
0.0020
B
Vest4
0.17
MutPred
0.30
Gain of phosphorylation at A158 (P = 0.012);
MVP
0.51
MPC
1.1
ClinPred
0.091
T
GERP RS
2.6
Varity_R
0.048
gMVP
0.61

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.

Other links and lift over

dbSNP: rs1937916185; hg19: chr12-49936515; API