rs1554083355

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.55

Publications

0 publications found

Variant links:

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)

KCNN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN2	NM_021614.4 link	c.724G>C	p.Glu242Gln	missense_variant	Exon 1 of 8	ENST00000673685.1	NP_067627.3	Q9H2S1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNN2	ENST00000673685.1 link	c.724G>C	p.Glu242Gln	missense_variant	Exon 1 of 8		NM_021614.4	ENSP00000501239.1	A0A669KBH3
KCNN2	ENST00000512097.10 link	c.922G>C	p.Glu308Gln	missense_variant	Exon 6 of 13	5		ENSP00000427120.4	A0A3F2YNY5
KCNN2	ENST00000631899.2 link	c.124G>C	p.Glu42Gln	missense_variant	Exon 1 of 9	5		ENSP00000487849.2	A0A0J9YW81
KCNN2	ENST00000507750.5 link	n.-246G>C		upstream_gene_variant		3		ENSP00000516687.1	A0A9L9PY74

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447654

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.00

AC:

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.00

AC:

AN:

86048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110936

Other (OTH)

AF:

0.00

AC:

AN:

60158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

.;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

.;M

PhyloP100

7.6

PrimateAI

Pathogenic

0.84

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

GERP RS

5.7

PromoterAI

-0.010

Neutral

(source)

Varity_R

0.33

gMVP

0.69

Mutation Taster

=59/41

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over