Variant 3-19390628-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_144633.3(KCNH8):c.959A>G(p.Asn320Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,612,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

KCNH8
NM_144633.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.51

Variant links:

Genes affected

KCNH8 (HGNC:18864): (potassium voltage-gated channel subfamily H member 8) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit. [provided by RefSeq, Jul 2008]

KCNH8 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity KCNH8_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH8	NM_144633.3 linkuse as main transcript	c.959A>G	p.Asn320Ser	missense_variant	6/16	ENST00000328405.7
LOC105376982	XR_940640.3 linkuse as main transcript	n.2924T>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH8	ENST00000328405.7 linkuse as main transcript	c.959A>G	p.Asn320Ser	missense_variant	6/16	1	NM_144633.3	P1	Q96L42-1
	ENST00000670571.1 linkuse as main transcript	n.962T>C		non_coding_transcript_exon_variant	6/6

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250206

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135224

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1460672

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726612

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

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

Dec 16, 2023

The c.959A>G (p.N320S) alteration is located in exon 6 (coding exon 6) of the KCNH8 gene. This alteration results from a A to G substitution at nucleotide position 959, causing the asparagine (N) at amino acid position 320 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

0.18

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Benign

-0.12

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.68

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.63

Sift

Benign

0.25

Sift4G

Benign

0.22

Polyphen

0.94

Vest4

0.50

MutPred

0.57

Loss of sheet (P = 0.0817);

MVP

0.90

MPC

1.0

ClinPred

0.88

GERP RS

5.4

Varity_R

0.19

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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