NM_172107.4:c.1232C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_172107.4(KCNQ2):​c.1232C>T​(p.Pro411Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000009 in 1,556,060 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

KCNQ2
NM_172107.4 missense

Scores

2
7
10

Clinical Significance

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

Conservation

PhyloP100: 5.07
Variant links:
Genes affected
KCNQ2 (HGNC:6296): (potassium voltage-gated channel subfamily Q member 2) The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2
Missense variant in the KCNQ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 319 curated pathogenic missense variants (we use a threshold of 10). The gene has 78 curated benign missense variants. Gene score misZ: 4.0411 (above the threshold of 3.09). Trascript score misZ: 3.6968 (above the threshold of 3.09). GenCC associations: The gene is linked to seizures, benign familial neonatal, 1, neonatal-onset developmental and epileptic encephalopathy, benign familial neonatal-infantile seizures, benign neonatal seizures, malignant migrating partial seizures of infancy, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, developmental and epileptic encephalopathy, 7, benign familial infantile epilepsy.
BP4
Computational evidence support a benign effect (MetaRNN=0.2690724).
BP6
Variant 20-63424192-G-A is Benign according to our data. Variant chr20-63424192-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461404.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ2NM_172107.4 linkc.1232C>T p.Pro411Leu missense_variant Exon 11 of 17 ENST00000359125.7 NP_742105.1 O43526-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ2ENST00000359125.7 linkc.1232C>T p.Pro411Leu missense_variant Exon 11 of 17 1 NM_172107.4 ENSP00000352035.2 O43526-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152176
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000184
AC:
3
AN:
162788
Hom.:
0
AF XY:
0.0000350
AC XY:
3
AN XY:
85828
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:
0.000130
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000784
AC:
11
AN:
1403766
Hom.:
0
Cov.:
31
AF XY:
0.0000115
AC XY:
8
AN XY:
692668
show subpopulations
Gnomad4 AFR exome
AF:
0.0000311
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000629
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000462
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152294
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.0000481
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000287
AC:
3

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Nov 15, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1232C>T (p.P411L) alteration is located in exon 11 (coding exon 11) of the KCNQ2 gene. This alteration results from a C to T substitution at nucleotide position 1232, causing the proline (P) at amino acid position 411 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1
Oct 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Benign
23
DANN
Benign
0.94
DEOGEN2
Benign
0.34
.;.;T;T;T;T;D;T;.;.
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.14
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.92
D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Benign
0.27
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.77
D
MutationAssessor
Benign
1.9
L;.;.;.;.;.;L;.;.;L
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-2.4
.;.;.;.;N;.;D;.;D;.
REVEL
Uncertain
0.48
Sift
Benign
0.35
.;.;.;.;T;.;T;.;T;.
Sift4G
Benign
0.14
T;D;T;T;T;.;T;T;T;T
Polyphen
0.0090
B;.;.;.;.;.;B;.;B;B
Vest4
0.51
MutPred
0.25
Loss of glycosylation at P411 (P = 0.0076);.;.;.;.;.;Loss of glycosylation at P411 (P = 0.0076);.;.;Loss of glycosylation at P411 (P = 0.0076);
MVP
0.88
MPC
0.65
ClinPred
0.31
T
GERP RS
4.5
Varity_R
0.10
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs754682495; hg19: chr20-62055545; API