Genetic Variant NM_012284.3:c.775G>A (chr12-49543470-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012284.3(KCNH3):c.775G>A(p.Gly259Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,601,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

KCNH3
NM_012284.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.07

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03281626).

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH3	NM_012284.3 link	c.775G>A	p.Gly259Ser	missense_variant	Exon 5 of 15	ENST00000257981.7	NP_036416.1	Q9ULD8
KCNH3	NM_001314030.2 link	c.595G>A	p.Gly199Ser	missense_variant	Exon 5 of 15		NP_001300959.1	Q9ULD8
KCNH3	XM_011538085.3 link	c.775G>A	p.Gly259Ser	missense_variant	Exon 5 of 15		XP_011536387.1
KCNH3	XM_047428613.1 link	c.775G>A	p.Gly259Ser	missense_variant	Exon 5 of 10		XP_047284569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNH3	ENST00000257981.7 link	c.775G>A	p.Gly259Ser	missense_variant	Exon 5 of 15	1	NM_012284.3	ENSP00000257981.5	Q9ULD8
KCNH3	ENST00000550434.1 link	n.504G>A		non_coding_transcript_exon_variant	Exon 4 of 5	3
KCNH3	ENST00000649994.1 link	n.*385G>A		non_coding_transcript_exon_variant	Exon 6 of 16			ENSP00000497890.1	A0A3B3ITH0
KCNH3	ENST00000649994.1 link	n.*385G>A		3_prime_UTR_variant	Exon 6 of 16			ENSP00000497890.1	A0A3B3ITH0

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

240438

Hom.:

AF XY:

0.0000763

AC XY:

AN XY:

131112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000275

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000166

AC:

240

AN:

1449044

Hom.:

Cov.:

AF XY:

0.000159

AC XY:

115

AN XY:

721164

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000241

Gnomad4 NFE exome

AF:

0.000202

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.000118

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000145

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000907

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.775G>A (p.G259S) alteration is located in exon 5 (coding exon 5) of the KCNH3 gene. This alteration results from a G to A substitution at nucleotide position 775, causing the glycine (G) at amino acid position 259 to be replaced by a serine (S). 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

0.077

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.23

CADD

Benign

7.1

DANN

Benign

0.46

DEOGEN2

Benign

0.41

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.73

M_CAP

Benign

0.073

MetaRNN

Benign

0.033

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

-1.8

PrimateAI

Uncertain

0.49

PROVEAN

Benign

1.4

REVEL

Benign

0.23

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.011

Vest4

0.19

MVP

0.61

MPC

1.1

ClinPred

0.011

GERP RS

1.6

Varity_R

0.033

gMVP

0.34

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