rs1365594917

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001386974.1(KCNN1):​c.451G>A​(p.Ala151Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KCNN1
NM_001386974.1 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.436

Publications

0 publications found
Variant links:
Genes affected
KCNN1 (HGNC:6290): (potassium calcium-activated channel subfamily N member 1) Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. The protein encoded by this gene is activated before membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. This gene is a member of the KCNN family of potassium channel genes. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.103933394).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNN1NM_001386974.1 linkc.451G>A p.Ala151Thr missense_variant Exon 3 of 10 ENST00000684775.1 NP_001373903.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNN1ENST00000684775.1 linkc.451G>A p.Ala151Thr missense_variant Exon 3 of 10 NM_001386974.1 ENSP00000507021.1 Q92952-1

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151824
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461614
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727106
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53376
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111818
Other (OTH)
AF:
0.00
AC:
0
AN:
60362
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151824
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74136
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41294
American (AMR)
AF:
0.00
AC:
0
AN:
15240
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4788
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10594
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67940
Other (OTH)
AF:
0.00
AC:
0
AN:
2078
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 18, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.451G>A (p.A151T) alteration is located in exon 4 (coding exon 2) of the KCNN1 gene. This alteration results from a G to A substitution at nucleotide position 451, causing the alanine (A) at amino acid position 151 to be replaced by a threonine (T). 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
0.11
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
8.9
DANN
Benign
0.97
DEOGEN2
Benign
0.25
T;.
Eigen
Benign
-0.89
Eigen_PC
Benign
-0.95
FATHMM_MKL
Benign
0.095
N
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.0099
T
MetaRNN
Benign
0.10
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.6
L;.
PhyloP100
-0.44
PrimateAI
Benign
0.29
T
REVEL
Benign
0.046
Sift4G
Benign
0.089
T;T
Polyphen
0.0020
B;.
Vest4
0.39
MutPred
0.49
Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);
MVP
0.10
MPC
0.51
ClinPred
0.11
T
GERP RS
1.5
Varity_R
0.032
gMVP
0.72
Mutation Taster
=90/10
polymorphism

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

Other links and lift over

dbSNP: rs1365594917; hg19: chr19-18085949; API