19-43769551-A-G

Position:

• chr19-43769551-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_002250.3(KCNN4):​c.940T>C​(p.Ser314Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNN4 NM_002250.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.57

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-43769551-A-G is Pathogenic according to our data. Variant chr19-43769551-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 978810.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNN4	NM_002250.3	c.940T>C	p.Ser314Pro	missense_variant	6/9	ENST00000648319.1	NP_002241.1
KCNN4	XM_005258882.3	c.844T>C	p.Ser282Pro	missense_variant	5/8		XP_005258939.1
KCNN4	XM_005258883.3	c.751T>C	p.Ser251Pro	missense_variant	6/9		XP_005258940.1
KCNN4	XM_047438794.1	c.268T>C	p.Ser90Pro	missense_variant	4/7		XP_047294750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNN4	ENST00000648319.1	c.940T>C	p.Ser314Pro	missense_variant	6/9		NM_002250.3	ENSP00000496939	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

UOS Fisiopatologia delle Anemie, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano

Aug 28, 2020

The p. S314P variant in KCNN4 gene has been reported in 7 Italian patients from 2 unrelated families presenting mild hemolytic anemia. In vitro functional studies indicate that the S314P variant result in a gain of function mutation and in increase activation of the Gardos channel. The variant meets criteria to be classified as pathogenic based upon segregation studies, absence from controls, phenotypic and functional evidence -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;D;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L;.;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	.;.;D
REVEL	Benign	0.27
Sift	Uncertain	0.0030	.;.;D
Sift4G	Uncertain	0.0050	.;D;D
Polyphen		0.99	D;.;D
Vest4		0.66, 0.61
MutPred		0.61		Loss of MoRF binding (P = 0.0495);.;Loss of MoRF binding (P = 0.0495);
MVP		0.85
MPC		1.6
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.85
gMVP		0.90

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

Other links and lift over

dbSNP: rs1969582489; hg19: chr19-44273703;