Genetic Variant KCNN2:p.Asp240Tyr (chr5-114362857-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_021614.4(KCNN2):c.718G>T(p.Asp240Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000025 in 1,599,892 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNN2
NM_021614.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.18

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 links:

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ACMG classification

Classification made for transcript

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 link	c.718G>T	p.Asp240Tyr	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.718G>T	p.Asp240Tyr	missense_variant	Exon 1 of 8		NM_021614.4	ENSP00000501239.1	A0A669KBH3
KCNN2	ENST00000512097.10 link	c.916G>T	p.Asp306Tyr	missense_variant	Exon 6 of 13	5		ENSP00000427120.4	A0A3F2YNY5
KCNN2	ENST00000631899.2 link	c.118G>T	p.Asp40Tyr	missense_variant	Exon 1 of 9	5		ENSP00000487849.2	A0A0J9YW81
KCNN2	ENST00000507750.5 link	n.-252G>T		upstream_gene_variant		3		ENSP00000516687.1	A0A9L9PY74

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000861

AC:

AN:

232216

Hom.:

AF XY:

0.00000782

AC XY:

AN XY:

127842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000189

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1447730

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720504

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

.;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.79

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

.;M

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.4

.;N

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.0040

.;D

Polyphen

1.0

.;D

Vest4

0.58

MutPred

0.22

.;Gain of phosphorylation at D28 (P = 0.0073);

MVP

0.77

MPC

0.75

ClinPred

0.98

GERP RS

5.7

Varity_R

0.54

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over