rs1057519077

chr19-43769804-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_002250.3(KCNN4):c.845T>A(p.Val282Glu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V282M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNN4 NM_002250.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.18

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-43769805-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372185.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 19-43769804-A-T is Pathogenic according to our data. Variant chr19-43769804-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372186.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNN4	NM_002250.3	c.845T>A	p.Val282Glu	missense_variant	5/9	ENST00000648319.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNN4	ENST00000648319.1	c.845T>A	p.Val282Glu	missense_variant	5/9		NM_002250.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dehydrated hereditary stomatocytosis 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 11, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 13, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.4	M;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
Polyphen		0.99	D;.;D
Vest4		0.95, 0.96
MutPred		0.80		Loss of stability (P = 0.1029);.;Loss of stability (P = 0.1029);
MVP		0.92
MPC		1.8
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

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: rs1057519077; hg19: chr19-44273956;