rs774455945

Positions:

• chr19-43769027-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.92

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]

ACMG classification

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/exons	MANE	Protein	UniProt
KCNN4	NM_002250.3	c.1055G>A	p.Arg352His	missense_variant	7/9	ENST00000648319.1	NP_002241.1
KCNN4	XM_005258882.3	c.959G>A	p.Arg320His	missense_variant	6/8		XP_005258939.1
KCNN4	XM_005258883.3	c.866G>A	p.Arg289His	missense_variant	7/9		XP_005258940.1
KCNN4	XM_047438794.1	c.383G>A	p.Arg128His	missense_variant	5/7		XP_047294750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNN4	ENST00000648319.1	c.1055G>A	p.Arg352His	missense_variant	7/9		NM_002250.3	ENSP00000496939	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461752 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 10, 2023	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNN4 protein function. Experimental studies have shown that this missense change affects KCNN4 function (PMID: 26148990). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2020	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) -

Dehydrated hereditary stomatocytosis 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 13, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:26148990, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.889, PP3_P). A missense variant is a common mechanism associated with Dehydrated hereditary stomatocytosis 2 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000252601, PMID:26148990, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
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	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
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	D
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

Other links and lift over

dbSNP: rs774455945; hg19: chr19-44273179; COSMIC: COSV53457124; COSMIC: COSV53457124;