19-43769473-G-T

Position:

chr19-43769473-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBP6BS2

The NM_002250.3(KCNN4):c.1018C>A(p.His340Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,614,232 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

KCNN4
NM_002250.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 9.51

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:

KCNN4 (HGNC:):

KCNN4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.068529695).

BP6

Variant 19-43769473-G-T is Benign according to our data. Variant chr19-43769473-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2007816.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 146 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KCNN4	NM_002250.3 linkuse as main transcript	c.1018C>A	p.His340Asn	missense_variant	6/9	ENST00000648319.1	NP_002241.1
KCNN4	XM_005258882.3 linkuse as main transcript	c.922C>A	p.His308Asn	missense_variant	5/8		XP_005258939.1
KCNN4	XM_005258883.3 linkuse as main transcript	c.829C>A	p.His277Asn	missense_variant	6/9		XP_005258940.1
KCNN4	XM_047438794.1 linkuse as main transcript	c.346C>A	p.His116Asn	missense_variant	4/7		XP_047294750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNN4	ENST00000648319.1 linkuse as main transcript	c.1018C>A	p.His340Asn	missense_variant	6/9		NM_002250.3	ENSP00000496939.1		O15554

Frequencies

GnomAD3 genomes

AF:

0.000965

AC:

147

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00154

AC:

387

AN:

251420

Hom.:

AF XY:

0.00148

AC XY:

201

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00170

Gnomad FIN exome

AF:

0.000740

Gnomad NFE exome

AF:

0.00145

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00122

AC:

1781

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

910

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00221

Gnomad4 ASJ exome

AF:

0.00589

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00196

Gnomad4 FIN exome

AF:

0.000618

Gnomad4 NFE exome

AF:

0.00105

Gnomad4 OTH exome

AF:

0.00179

GnomAD4 genome

AF:

0.000958

AC:

146

AN:

152372

Hom.:

Cov.:

AF XY:

0.000859

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.00115

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00139

AC:

169

EpiCase

AF:

0.00229

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 02, 2023	PP3, PS3 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2023	Reported in two probands with clinical suspicion of hereditary erythrocyte defects, but parental segregation information was not provided and both individuals were reported to have potentially causative variants in other genes as well (Andolfo et al., 2021); Reported in an individual with transient anemia in infancy, but the variant was inherited from an asymptomatic mother (Allegrini et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34201899, 36003639) -

KCNN4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

D;D;D

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.069

T;T;T

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.8

M;.;M

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.6

.;.;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

.;.;D

Sift4G

Uncertain

0.0060

.;D;D

Polyphen

1.0

D;.;D

Vest4

0.74, 0.66

MVP

0.99

MPC

1.5

ClinPred

0.078

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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