5-114362672-C-T

Position:

• chr5-114362672-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_021614.4(KCNN2):​c.533C>T​(p.Ser178Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,275,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/10 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)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: KCNN2 NM_021614.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30933553).
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNN2	NM_021614.4	c.533C>T	p.Ser178Phe	missense_variant	1/8	ENST00000673685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNN2	ENST00000673685.1	c.533C>T	p.Ser178Phe	missense_variant	1/8		NM_021614.4	P2
KCNN2	ENST00000512097.10	c.731C>T	p.Ser244Phe	missense_variant	6/13	5		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000204 AC: 26 AN: 1275542 Hom.: 0 Cov.: 25 AF XY: 0.0000257 AC XY: 16 AN XY: 621720

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000300

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000684

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with or without variable movement or behavioral abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed missense c.533C>T(p.Ser178Phe) variant in KCNN2 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Ser178Phe variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Multiple lines of computational evidences (SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 178 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Benign	0.96
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.31	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-3.6	D
Sift	Uncertain	0.017	D
GERP RS		4.1

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: chr5-113698369;