Variant 12-49541019-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BS2

The NM_012284.3(KCNH3):c.197C>A(p.Ala66Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

KCNH3
NM_012284.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH3	NM_012284.3 link	c.197C>A	p.Ala66Asp	missense_variant	2/15	ENST00000257981.7	NP_036416.1	Q9ULD8
KCNH3	NM_001314030.2 link	c.17C>A	p.Ala6Asp	missense_variant	2/15		NP_001300959.1	Q9ULD8
KCNH3	XM_011538085.3 link	c.197C>A	p.Ala66Asp	missense_variant	2/15		XP_011536387.1
KCNH3	XM_047428613.1 link	c.197C>A	p.Ala66Asp	missense_variant	2/10		XP_047284569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH3	ENST00000257981.7 link	c.197C>A	p.Ala66Asp	missense_variant	2/15	1	NM_012284.3	ENSP00000257981.5		Q9ULD8
KCNH3	ENST00000649994.1 link	n.197C>A		non_coding_transcript_exon_variant	2/16			ENSP00000497890.1		A0A3B3ITH0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727134

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Oct 17, 2024

The c.197C>A (p.A66D) alteration is located in exon 2 (coding exon 2) of the KCNH3 gene. This alteration results from a C to A substitution at nucleotide position 197, causing the alanine (A) at amino acid position 66 to be replaced by an aspartic acid (D). 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

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.51

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.2

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.016

Polyphen

0.26

Vest4

0.52

MutPred

0.57

Gain of relative solvent accessibility (P = 0.09);

MVP

0.96

MPC

2.6

ClinPred

0.98

GERP RS

5.1

Varity_R

0.60

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over