5-114362863-G-C

Variant names:

• chr5-114362863-G-C
• rs1554083355
• NM_021614.4:c.724G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021614.4(KCNN2):​c.724G>C​(p.Glu242Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNN2 NM_021614.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN2	NM_021614.4	c.724G>C	p.Glu242Gln	missense_variant	Exon 1 of 8	ENST00000673685.1	NP_067627.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN2	ENST00000673685.1	c.724G>C	p.Glu242Gln	missense_variant	Exon 1 of 8		NM_021614.4	ENSP00000501239.1
KCNN2	ENST00000512097.10	c.922G>C	p.Glu308Gln	missense_variant	Exon 6 of 13	5		ENSP00000427120.4
KCNN2	ENST00000631899.2	c.124G>C	p.Glu42Gln	missense_variant	Exon 1 of 9	5		ENSP00000487849.2
KCNN2	ENST00000507750.5	n.-246G>C		upstream_gene_variant		3		ENSP00000516687.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447654 Hom.: 0 Cov.: 76 AF XY: 0.00 AC XY: 0 AN XY: 720520

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.88G>C (p.E30Q) alteration is located in exon 1 (coding exon 1) of the KCNN2 gene. This alteration results from a G to C substitution at nucleotide position 88, causing the glutamic acid (E) at amino acid position 30 to be replaced by a glutamine (Q). Based on data from the Genome Aggregation Database (gnomAD), the KCNN2 c.88G>C alteration was not observed, with coverage at this position. This alteration was reported de novo in a patient with epileptic encephalopathy, tremor, dystonia, dyskinesia, and seizures (Mochel, 2020). This amino acid position is highly conserved in available vertebrate species. The p.E30 amino acid is located at the N-terminal of the protein, which is predicted to contain the mitochondrial targeting sequence by in silico prediction tools (Dolga, 2013). However, this domain has not been functionally characterized. The in silico prediction for the p.E30Q alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.55	.;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0050	.;D
Sift4G	Uncertain	0.054	.;T
Polyphen		0.99	.;D
Vest4		0.38
MutPred		0.076		.;Gain of MoRF binding (P = 0.0574);
MVP		0.80
MPC		0.54
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.33
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554083355; hg19: chr5-113698560;