rs1554086554

Variant names:

• chr5-114404814-CATT-C
• rs1554086554
• NM_021614.4:c.1598_1600delTAT

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PM4_Supporting PP5_Very_Strong

The NM_021614.4(KCNN2):​c.1598_1600delTAT​(p.Leu533del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000742826: 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)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNN2 NM_021614.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.00
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with or without variable movement or behavioral abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000742826: 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).; SCV004118627: 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).
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 521994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021614.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN2	NM_021614.4	MANE Select	c.1598_1600delTAT	p.Leu533del	disruptive_inframe_deletion	Exon 3 of 8	NP_067627.3
	KCNN2	NM_001372233.1		c.1796_1798delTAT	p.Leu599del	disruptive_inframe_deletion	Exon 8 of 13	NP_001359162.1	A0A3F2YNY5
	KCNN2	NR_174097.1		n.1288+40816_1288+40818delTAT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN2	ENST00000673685.1	MANE Select	c.1598_1600delTAT	p.Leu533del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000501239.1	A0A669KBH3
	KCNN2	ENST00000512097.10	TSL:5	c.1796_1798delTAT	p.Leu599del	disruptive_inframe_deletion	Exon 8 of 13	ENSP00000427120.4	A0A3F2YNY5
	KCNN2	ENST00000631899.2	TSL:5	c.998_1000delTAT	p.Leu333del	disruptive_inframe_deletion	Exon 3 of 9	ENSP00000487849.2	A0A0J9YW81

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Global developmental delay (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	KCNN2-related disorder (1)
1	-	-	Neurodevelopmental disorder with or without variable movement or behavioral abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=27/73	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554086554; hg19: chr5-113740511;