5-114362492-C-T

Position:

• chr5-114362492-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_021614.4(KCNN2):​c.353C>T​(p.Ser118Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00033 in 466,008 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S118S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: KCNN2 NM_021614.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23983023).
• BS2: High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNN2	NM_021614.4	c.353C>T	p.Ser118Leu	missense_variant	1/8	ENST00000673685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNN2	ENST00000673685.1	c.353C>T	p.Ser118Leu	missense_variant	1/8		NM_021614.4	P2
KCNN2	ENST00000512097.10	c.551C>T	p.Ser184Leu	missense_variant	6/13	5		A2

Frequencies

GnomAD3 genomes AF: 0.000244 AC: 37 AN: 151938 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000373 AC: 117 AN: 313962 Hom.: 1 Cov.: 3 AF XY: 0.000387 AC XY: 63 AN XY: 162846

Gnomad4 AFR exome AF: 0.000290

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00379

Gnomad4 EAS exome AF: 0.0000452

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.000923

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152046 Hom.: 0 Cov.: 33 AF XY: 0.000283 AC XY: 21 AN XY: 74332

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000246

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

-

The missense c.353C>Tp.Ser118Leu variant in KCNN2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser118Leu variant has been reported with allele frequency of 0.01% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes database. This variant has not been reported to the ClinVar database. The amino acid change p.Ser118Leu in KCNN2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 118 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	0.98
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.24	T
MutationTaster	Benign	1.0	D;D
GERP RS		5.0

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

LitVar

Other links and lift over

dbSNP: rs544525765; hg19: chr5-113698189;