5-114362863-GAG-CAA

Variant names:

• chr5-114362863-GAG-CAA
• NM_021614.4:c.724_726delGAGinsCAA
• KCNN2 p.Glu242Gln

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2 PP3

The NM_021614.4(KCNN2):​c.724_726delGAGinsCAA​(p.Glu242Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNN2 NM_021614.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.55
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.2857 (below the threshold of 3.09). Trascript score misZ: 1.564 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with or without variable movement or behavioral abnormalities.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.724_726delGAGinsCAA	p.Glu242Gln	missense	N/A	NP_067627.3
	KCNN2	NM_001372233.1		c.922_924delGAGinsCAA	p.Glu308Gln	missense	N/A	NP_001359162.1	A0A3F2YNY5
	KCNN2	NR_174097.1		n.794_796delGAGinsCAA		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN2	ENST00000673685.1	MANE Select	c.724_726delGAGinsCAA	p.Glu242Gln	missense	N/A	ENSP00000501239.1	A0A669KBH3
	KCNN2	ENST00000512097.10	TSL:5	c.922_924delGAGinsCAA	p.Glu308Gln	missense	N/A	ENSP00000427120.4	A0A3F2YNY5
	KCNN2	ENST00000631899.2	TSL:5	c.124_126delGAGinsCAA	p.Glu42Gln	missense	N/A	ENSP00000487849.2	A0A0J9YW81

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-113698560;