chr5-114362470-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021614.4(KCNN2):​c.331T>G​(p.Ser111Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

KCNN2
NM_021614.4 missense

Scores

2
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87
Variant links:
Genes affected
KCNN2 (HGNC:6291): (potassium calcium-activated channel subfamily N member 2) 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. This gene is a member of the KCNN family of potassium channel genes. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. Alternate splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24500597).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNN2NM_021614.4 linkuse as main transcriptc.331T>G p.Ser111Ala missense_variant 1/8 ENST00000673685.1 NP_067627.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNN2ENST00000673685.1 linkuse as main transcriptc.331T>G p.Ser111Ala missense_variant 1/8 NM_021614.4 ENSP00000501239 P2
KCNN2ENST00000512097.10 linkuse as main transcriptc.529T>G p.Ser177Ala missense_variant 6/135 ENSP00000427120 A2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
3
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Neurodevelopmental disorder with or without variable movement or behavioral abnormalities Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The missense c.331T>G(p.Ser111Ala) variant in KCNN2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in gnomAD Exomes and 1000 Genomes. The amino acid Ser at position 111 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser111Ala in KCNN2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.40
CADD
Benign
22
DANN
Benign
0.93
FATHMM_MKL
Benign
0.49
N
LIST_S2
Benign
0.32
T
MetaRNN
Benign
0.25
T
MutationTaster
Benign
1.0
D;D
PROVEAN
Uncertain
-2.7
D
Sift
Uncertain
0.0020
D
GERP RS
5.3

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.

Other links and lift over

hg19: chr5-113698167; API