Variant 19-43767572-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002250.3(KCNN4):c.1255C>T(p.Leu419Phe) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

KCNN4
NM_002250.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05

Variant links:

Genes affected

KCNN4 (HGNC:6293): (potassium calcium-activated channel subfamily N member 4) The protein encoded by this gene is part of a potentially heterotetrameric voltage-independent potassium channel that is activated by intracellular calcium. Activation is followed by membrane hyperpolarization, which promotes calcium influx. The encoded protein may be part of the predominant calcium-activated potassium channel in T-lymphocytes. This gene is similar to other KCNN family potassium channel genes, but it differs enough to possibly be considered as part of a new subfamily. [provided by RefSeq, Jul 2008]

KCNN4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14643386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KCNN4	NM_002250.3 linkuse as main transcript	c.1255C>T	p.Leu419Phe	missense_variant	8/9	ENST00000648319.1	NP_002241.1
KCNN4	XM_005258882.3 linkuse as main transcript	c.1159C>T	p.Leu387Phe	missense_variant	7/8		XP_005258939.1
KCNN4	XM_005258883.3 linkuse as main transcript	c.1066C>T	p.Leu356Phe	missense_variant	8/9		XP_005258940.1
KCNN4	XM_047438794.1 linkuse as main transcript	c.583C>T	p.Leu195Phe	missense_variant	6/7		XP_047294750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNN4	ENST00000648319.1 linkuse as main transcript	c.1255C>T	p.Leu419Phe	missense_variant	8/9		NM_002250.3	ENSP00000496939	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250742

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135534

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2024

The c.1255C>T (p.L419F) alteration is located in exon 8 (coding exon 8) of the KCNN4 gene. This alteration results from a C to T substitution at nucleotide position 1255, causing the leucine (L) at amino acid position 419 to be replaced by a phenylalanine (F). 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

Benign

0.080

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;T;T;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.69

T;.;T;T

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Pathogenic

1.6

MutationAssessor

Benign

1.5

.;L;.;L

MutationTaster

Benign

0.84

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

.;.;.;N

REVEL

Uncertain

0.40

Sift

Benign

0.035

.;.;.;D

Sift4G

Benign

0.21

T;.;D;T

Polyphen

0.43

.;B;.;B

Vest4

0.17, 0.12

MutPred

0.15

.;Loss of catalytic residue at L419 (P = 0.01);.;Loss of catalytic residue at L419 (P = 0.01);

MVP

0.91

MPC

0.98

ClinPred

0.28

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.058

gMVP

0.12

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over