Variant 12-49544262-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_012284.3(KCNH3):c.1069G>A(p.Ala357Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000686 in 1,607,350 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00072 ( 2 hom. )

Consequence

KCNH3
NM_012284.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.72

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:

KCNH3 (HGNC:):

KCNH3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH3	NM_012284.3 linkuse as main transcript	c.1069G>A	p.Ala357Thr	missense_variant	7/15	ENST00000257981.7	NP_036416.1	Q9ULD8
KCNH3	NM_001314030.2 linkuse as main transcript	c.889G>A	p.Ala297Thr	missense_variant	7/15		NP_001300959.1	Q9ULD8
KCNH3	XM_011538085.3 linkuse as main transcript	c.1069G>A	p.Ala357Thr	missense_variant	7/15		XP_011536387.1
KCNH3	XM_047428613.1 linkuse as main transcript	c.1069G>A	p.Ala357Thr	missense_variant	7/10		XP_047284569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNH3	ENST00000257981.7 linkuse as main transcript	c.1069G>A	p.Ala357Thr	missense_variant	7/15	1	NM_012284.3	ENSP00000257981.5	Q9ULD8
KCNH3	ENST00000551415.1 linkuse as main transcript	n.9G>A		non_coding_transcript_exon_variant	1/2	3
KCNH3	ENST00000649994.1 linkuse as main transcript	n.*679G>A		non_coding_transcript_exon_variant	8/16			ENSP00000497890.1	A0A3B3ITH0
KCNH3	ENST00000649994.1 linkuse as main transcript	n.*679G>A		3_prime_UTR_variant	8/16			ENSP00000497890.1	A0A3B3ITH0

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000326

AC:

AN:

239228

Hom.:

AF XY:

0.000330

AC XY:

AN XY:

130178

show subpopulations

Gnomad AFR exome

AF:

0.000265

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000336

Gnomad FIN exome

AF:

0.000105

Gnomad NFE exome

AF:

0.000639

Gnomad OTH exome

AF:

0.000339

GnomAD4 exome

AF:

0.000720

AC:

1047

AN:

1455176

Hom.:

Cov.:

AF XY:

0.000694

AC XY:

502

AN XY:

723782

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.0000452

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.000159

Gnomad4 NFE exome

AF:

0.000912

Gnomad4 OTH exome

AF:

0.000332

GnomAD4 genome

AF:

0.000368

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000479

Hom.:

Bravo

AF:

0.000321

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000362

AC:

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 submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.1069G>A (p.A357T) alteration is located in exon 7 (coding exon 7) of the KCNH3 gene. This alteration results from a G to A substitution at nucleotide position 1069, causing the alanine (A) at amino acid position 357 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

0.15

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.47

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.6

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.54

Sift

Benign

0.23

Sift4G

Benign

0.28

Polyphen

0.61

Vest4

0.60

MVP

0.90

MPC

1.8

ClinPred

0.091

GERP RS

4.7

Varity_R

0.13

gMVP

0.93

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