Variant rs1554774322 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The ENST00000371757.7(KCNT1):c.1406A>C(p.His469Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H469Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

KCNT1
ENST00000371757.7 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.18

Variant links:

Genes affected

KCNT1 (HGNC:18865): (potassium sodium-activated channel subfamily T member 1) Potassium 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 sodium-activated potassium channel subunit which is thought to function in ion conductance and developmental signaling pathways. Mutations in this gene cause the early-onset epileptic disorders, malignant migrating partial seizures of infancy and autosomal dominant nocturnal frontal lobe epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

KCNT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in ENST00000371757.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-135768833-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496671.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.843

PP5

Variant 9-135768833-A-C is Pathogenic according to our data. Variant chr9-135768833-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1320152.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNT1	NM_020822.3 linkuse as main transcript	c.1406A>C	p.His469Pro	missense_variant	15/31	ENST00000371757.7	NP_065873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNT1	ENST00000371757.7 linkuse as main transcript	c.1406A>C	p.His469Pro	missense_variant	15/31	1	NM_020822.3	ENSP00000360822	A2	Q5JUK3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 14

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Oct 02, 2021

It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.His469Leu) has been reported as pathogenic/likely pathogenic (VCV000496671.1 PM5). Missense changes are a common disease-causing mechanism (PP2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.641, 3Cnet: 0.907, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

.;.;.;.;.;.;.;.;T;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.1

.;.;.;.;.;.;.;.;L;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.0

.;.;D;D;.;.;.;.;D;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.024

.;.;D;D;.;.;.;.;D;D

Sift4G

Uncertain

0.026

D;D;D;D;D;D;D;D;D;D

Polyphen

0.93

.;.;.;.;.;.;.;.;P;.

Vest4

0.97

MutPred

0.54

.;.;.;.;.;.;Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);

MVP

0.81

MPC

1.9

ClinPred

1.0

GERP RS

3.5

Varity_R

0.89

gMVP

0.99

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over