Variant chr3-19395212-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_144633.3(KCNH8):c.1078A>T(p.Met360Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

KCNH8
NM_144633.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

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.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH8	NM_144633.3 linkuse as main transcript	c.1078A>T	p.Met360Leu	missense_variant	7/16	ENST00000328405.7	NP_653234.2
LOC105376982	XR_940640.3 linkuse as main transcript	n.2700-4360T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH8	ENST00000328405.7 linkuse as main transcript	c.1078A>T	p.Met360Leu	missense_variant	7/16	1	NM_144633.3	ENSP00000328813	P1	Q96L42-1
	ENST00000670571.1 linkuse as main transcript	n.738-4360T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1457232

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724784

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:

0.00

Gnomad4 OTH exome

AF:

0.0000997

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

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 03, 2022

The c.1078A>T (p.M360L) alteration is located in exon 7 (coding exon 7) of the KCNH8 gene. This alteration results from a A to T substitution at nucleotide position 1078, causing the methionine (M) at amino acid position 360 to be replaced by a leucine (L). 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

0.75

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

D;N

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0040

Sift4G

Benign

0.084

Polyphen

0.99

Vest4

0.72

MutPred

0.65

Loss of MoRF binding (P = 0.3846);

MVP

0.93

MPC

1.5

ClinPred

0.95

GERP RS

5.9

Varity_R

0.45

gMVP

0.81

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