rs1253410807

Variant names:

• chr5-114404518-A-G
• rs1253410807
• NM_021614.4:c.1299A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_021614.4(KCNN2):​c.1299A>G​(p.Ile433Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNN2 NM_021614.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• 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.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37043455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN2	NM_021614.4	c.1299A>G	p.Ile433Met	missense_variant	Exon 3 of 8	ENST00000673685.1	NP_067627.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN2	ENST00000673685.1	c.1299A>G	p.Ile433Met	missense_variant	Exon 3 of 8		NM_021614.4	ENSP00000501239.1
KCNN2	ENST00000512097.10	c.1497A>G	p.Ile499Met	missense_variant	Exon 8 of 13	5		ENSP00000427120.4
KCNN2	ENST00000631899.2	c.699A>G	p.Ile233Met	missense_variant	Exon 3 of 9	5		ENSP00000487849.2
KCNN2	ENST00000507750.5	n.249+40517A>G		intron_variant	Intron 2 of 6	3		ENSP00000516687.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 02, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.32	.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.093	D
MutationAssessor	Benign	-0.76	.;N
PhyloP100		1.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.10	.;N
REVEL	Uncertain	0.55
Sift	Benign	0.19	.;T
Sift4G	Benign	0.074	.;T
Polyphen		0.013	.;B
Vest4		0.74
MutPred		0.56		.;Gain of catalytic residue at I221 (P = 0.2837);
MVP		0.94
MPC		2.4
ClinPred		0.74	D
GERP RS		1.1
Varity_R		0.14
gMVP		0.90
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs1253410807; hg19: chr5-113740215;