chr5-114404814-CATT-C

Position:

• chr5-114404814-CATT-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_021614.4(KCNN2):​c.1598_1600del​(p.Leu533del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNN2 NM_021614.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.00

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_021614.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 5-114404814-CATT-C is Pathogenic according to our data. Variant chr5-114404814-CATT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNN2	NM_021614.4	c.1598_1600del	p.Leu533del	inframe_deletion	3/8	ENST00000673685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNN2	ENST00000673685.1	c.1598_1600del	p.Leu533del	inframe_deletion	3/8		NM_021614.4	P2
KCNN2	ENST00000512097.10	c.1796_1798del	p.Leu599del	inframe_deletion	8/13	5		A2
KCNN2	ENST00000631899.2	c.1000_1002del	p.Leu334del	inframe_deletion	3/9	5
KCNN2	ENST00000507750.5	c.251+40816_251+40818del		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Human Genetics, University Hospital Essen

Jul 01, 2020

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2021

The c.962_964delTAT (p.L321del) alteration is located in coding exon 3 of the KCNN2 gene. This alteration consists of an in-frame deletion of 3 nucleotides at positions 962 and 964, resulting in the deletion of a leucine at amino acid position 321. Based on data from the Genome Aggregation Database (gnomAD), the KCNN2 c.962_964delTAT alteration was not observed, with coverage at this position. This alteration was described to occur de novo in a 2 year old female with motor and language delay (Mochel, 2020). The p.L321 amino acid is conserved in available vertebrate species. The p.L321 amino acid is located within the S5 transmembrane alpha helix that forms part of the central pore domain of the KCNN2 (SK2) protein (NCBI). Structrural modeling performed at Ambry Genetics indicates that this deletion will effectively cause all of the amino acids on the helix to be shifted over by one residue placing side chains into the center of the pore and likely blocking it (Long, 2005). The p.L321del alteration is predicted to be highly deleterious with a score of -12.344 by PROVEAN in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

KCNN2-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 26, 2023

The KCNN2 c.962_964delTAT variant is predicted to result in an in-frame deletion (p.Leu321del). This variant was reported as de novo in an individual presenting with motor, language, and developmental delay without seizure or movement anomalies (Patient 4 in Mochel et al. 2020. PubMed ID: 33242881). Functional analysis showed that this variant lead to a reduced whole cell current when compared to wildtype KCNN2 (Mochel et al. 2020. PubMed ID: 33242881). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs1554086554; hg19: chr5-113740511;