Genetic Variant NM_012284.3:c.74C>T (chr12-49539490-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_012284.3(KCNH3):c.74C>T(p.Thr25Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNH3
NM_012284.3 missense, splice_region

Scores

Splicing: ADA: 0.9745

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.94

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KCNH3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012284.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNH3	NM_012284.3	MANE Select	c.74C>T	p.Thr25Met	missense splice_region	Exon 1 of 15	NP_036416.1	Q9ULD8
KCNH3	NM_001314030.2		c.-103C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001300959.1
KCNH3	NM_001314030.2		c.-103C>T		splice_region	Exon 1 of 15	NP_001300959.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNH3	ENST00000257981.7	TSL:1 MANE Select	c.74C>T	p.Thr25Met	missense splice_region	Exon 1 of 15	ENSP00000257981.5	Q9ULD8
KCNH3	ENST00000965158.1		c.74C>T	p.Thr25Met	missense splice_region	Exon 1 of 14	ENSP00000635217.1
KCNH3	ENST00000649994.1		n.74C>T		splice_region non_coding_transcript_exon	Exon 1 of 16	ENSP00000497890.1	A0A3B3ITH0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1435986

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714186

African (AFR)

AF:

0.00

AC:

AN:

31208

American (AMR)

AF:

0.00

AC:

AN:

41466

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25446

East Asian (EAS)

AF:

0.00

AC:

AN:

36138

South Asian (SAS)

AF:

0.00

AC:

AN:

83118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101298

Other (OTH)

AF:

0.00

AC:

AN:

59424

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.51

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.7

PhyloP100

2.9

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

0.74

Vest4

0.38

MutPred

0.37

Gain of helix (P = 0.0496)

MVP

0.94

MPC

1.3

ClinPred

0.99

GERP RS

3.3

PromoterAI

0.026

Neutral

(source)

Varity_R

0.49

gMVP

0.77

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.79

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over