Genetic Variant NM_012284.3:c.2786C>A (chr12-49557487-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_012284.3(KCNH3):c.2786C>A(p.Ala929Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KCNH3
NM_012284.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.807

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:

MCRS1 (HGNC:6960): (microspherule protein 1) Enables RNA binding activity and telomerase inhibitor activity. Involved in histone H4 acetylation; negative regulation of DNA metabolic process; and positive regulation of protein localization to nucleolus. Located in cytoplasm; nucleolus; and nucleoplasm. Part of Ino80 complex; MLL1 complex; and histone acetyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

MCRS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10913211).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH3	NM_012284.3 link	c.2786C>A	p.Ala929Asp	missense_variant	Exon 15 of 15	ENST00000257981.7	NP_036416.1	Q9ULD8
KCNH3	NM_001314030.2 link	c.2606C>A	p.Ala869Asp	missense_variant	Exon 15 of 15		NP_001300959.1	Q9ULD8
KCNH3	XM_011538085.3 link	c.2819C>A	p.Ala940Asp	missense_variant	Exon 15 of 15		XP_011536387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH3	ENST00000257981.7 link	c.2786C>A	p.Ala929Asp	missense_variant	Exon 15 of 15	1	NM_012284.3	ENSP00000257981.5		Q9ULD8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1459136

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725956

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.66

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.11

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.40

Sift

Uncertain

0.017

Sift4G

Benign

0.12

Polyphen

0.28

Vest4

0.24

MutPred

0.19

Loss of glycosylation at P928 (P = 0.1381);

MVP

0.50

MPC

0.26

ClinPred

0.18

GERP RS

4.0

Varity_R

0.14

gMVP

0.30

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over