5-114362471-C-CCTG

Position:

• chr5-114362471-C-CCTG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_Supporting BS1_Supporting BS2

The NM_021614.4(KCNN2):​c.350_352dupGCT​(p.Cys117dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 444,272 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.015 (22 hom., cov: 33)
  • Exomes 𝑓: 0.012 (15 hom.)
• Consequence: KCNN2 NM_021614.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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]

KCNN2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021614.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0145 (2211/152178) while in subpopulation NFE AF= 0.0172 (1166/67956). AF 95% confidence interval is 0.0163. There are 22 homozygotes in gnomad4. There are 1054 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2211 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNN2	NM_021614.4	c.350_352dupGCT	p.Cys117dup	disruptive_inframe_insertion	1/8	ENST00000673685.1	NP_067627.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNN2	ENST00000673685.1	c.350_352dupGCT	p.Cys117dup	disruptive_inframe_insertion	1/8		NM_021614.4	ENSP00000501239.1
KCNN2	ENST00000512097.10	c.548_550dupGCT	p.Cys183dup	disruptive_inframe_insertion	6/13	5		ENSP00000427120.4

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2208 AN: 152074 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.0123 AC: 3601 AN: 292094 Hom.: 15 Cov.: 0 AF XY: 0.0120 AC XY: 1822 AN XY: 151908

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.00485

Gnomad4 ASJ exome AF: 0.00292

Gnomad4 EAS exome AF: 0.0000984

Gnomad4 SAS exome AF: 0.00280

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0145 AC: 2211 AN: 152178 Hom.: 22 Cov.: 33 AF XY: 0.0142 AC XY: 1054 AN XY: 74392

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0204

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.0109

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 inframe insertion variant c.350_352dup(p.Cys117dup) in KCNN2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.350_352dup has 1.7% allele frequency in gnomAD Exomes. This variant p.Cys117dup causes duplication of amino acid Cysteine at postion 117. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs567706065; hg19: chr5-113698168;