Genetic Variant KCNN4:p.Arg352His (chr19-43769027-C-T) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_002250.3(KCNN4):c.1055G>A(p.Arg352His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNN4
NM_002250.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.92

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 19-43769027-C-T is Pathogenic according to our data. Variant chr19-43769027-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 252601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNN4	NM_002250.3 link	c.1055G>A	p.Arg352His	missense_variant	Exon 7 of 9	ENST00000648319.1	NP_002241.1
KCNN4	XM_005258882.3 link	c.959G>A	p.Arg320His	missense_variant	Exon 6 of 8		XP_005258939.1
KCNN4	XM_005258883.3 link	c.866G>A	p.Arg289His	missense_variant	Exon 7 of 9		XP_005258940.1
KCNN4	XM_047438794.1 link	c.383G>A	p.Arg128His	missense_variant	Exon 5 of 7		XP_047294750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN4	ENST00000648319.1 link	c.1055G>A	p.Arg352His	missense_variant	Exon 7 of 9		NM_002250.3	ENSP00000496939.1		O15554

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727184

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; Xenopus and transfected cells showed that the potassium channel exhibits a higher activity and a higher calcium sensitivity compared with the wild-type channel (Rapetti-Mauss et al., 2015); This variant is associated with the following publications: (PMID: 32641076, 30577886, 26148990, 26198474, 26178367, 28496185, 27443288) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNN4: PM6:Strong, PP1:Strong, PM2, PS4:Moderate, PS3:Supporting -

Apr 03, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PM1, PS3 -

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 352 of the KCNN4 protein (p.Arg352His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with xerocytosis (PMID: 26148990, 26178367, 28496185). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 252601). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNN4 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCNN4 function (PMID: 26148990). For these reasons, this variant has been classified as Pathogenic. -

Dehydrated hereditary stomatocytosis 2

Pathogenic:4

Jun 20, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2024

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.98 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013335 /PMID: 11992261 /3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Phe285Cys, p.Phe285Ile, p.Phe285Leu, p.Phe285Tyr, p.Phe285Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040527, VCV000040528, VCV000040533, VCV000044615, VCV000181499, VCV000636408, VCV001201246 /PMID: 11992261, 16358218, 17339163, 18678287, 30896080, 36703223 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 11, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 13, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D;D

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.4

M;.;M

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.7

.;.;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

.;.;D

Sift4G

Pathogenic

0.0010

.;D;D

Polyphen

0.99

D;.;D

Vest4

0.78, 0.56

MutPred

0.81

Loss of methylation at R352 (P = 0.0316);.;Loss of methylation at R352 (P = 0.0316);

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.82

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