rs376758763

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_020822.3(KCNT1):​c.2527G>A​(p.Asp843Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000941 in 1,550,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

KCNT1
NM_020822.3 missense

Scores

1
7
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 9.65
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.201121).
BP6
Variant 9-135778428-G-A is Benign according to our data. Variant chr9-135778428-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 833602.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNT1NM_020822.3 linkuse as main transcriptc.2527G>A p.Asp843Asn missense_variant 22/31 ENST00000371757.7 NP_065873.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNT1ENST00000371757.7 linkuse as main transcriptc.2527G>A p.Asp843Asn missense_variant 22/311 NM_020822.3 ENSP00000360822 A2Q5JUK3-3

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000565
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000897
AC:
14
AN:
156076
Hom.:
0
AF XY:
0.0000609
AC XY:
5
AN XY:
82164
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000404
Gnomad ASJ exome
AF:
0.000117
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000401
Gnomad NFE exome
AF:
0.0000827
Gnomad OTH exome
AF:
0.000226
GnomAD4 exome
AF:
0.0000929
AC:
130
AN:
1398712
Hom.:
0
Cov.:
32
AF XY:
0.0000884
AC XY:
61
AN XY:
689878
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000280
Gnomad4 ASJ exome
AF:
0.0000397
Gnomad4 EAS exome
AF:
0.0000280
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000577
Gnomad4 NFE exome
AF:
0.0000843
Gnomad4 OTH exome
AF:
0.000138
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152178
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000565
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000409
Hom.:
0
Bravo
AF:
0.0000567
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000123
AC:
1
ExAC
AF:
0.0000561
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 19, 2020In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Developmental and epileptic encephalopathy, 14;C3554306:Autosomal dominant nocturnal frontal lobe epilepsy 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 10, 2023- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 16, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
.;.;.;.;.;.;.;.;T;.
Eigen
Benign
0.12
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.095
D
MetaRNN
Benign
0.20
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.46
T
MutationAssessor
Benign
1.4
.;.;.;.;.;.;.;.;L;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-2.6
.;.;D;.;.;.;.;.;N;N
REVEL
Uncertain
0.36
Sift
Benign
0.29
.;.;T;.;.;.;.;.;T;T
Sift4G
Benign
0.29
T;T;T;T;T;T;T;T;T;T
Polyphen
0.17
.;.;.;.;.;.;.;.;B;.
Vest4
0.42
MVP
0.82
MPC
0.64
ClinPred
0.19
T
GERP RS
4.7
Varity_R
0.29
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs376758763; hg19: chr9-138670274; COSMIC: COSV53713445; API