19-43767668-T-G

Variant names:

• chr19-43767668-T-G
• rs1466617448
• NM_002250.3:c.1159A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002250.3(KCNN4):​c.1159A>C​(p.Ser387Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNN4 NM_002250.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.144

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11851174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN4	NM_002250.3	c.1159A>C	p.Ser387Arg	missense_variant	Exon 8 of 9	ENST00000648319.1	NP_002241.1
KCNN4	XM_005258882.3	c.1063A>C	p.Ser355Arg	missense_variant	Exon 7 of 8		XP_005258939.1
KCNN4	XM_005258883.3	c.970A>C	p.Ser324Arg	missense_variant	Exon 8 of 9		XP_005258940.1
KCNN4	XM_047438794.1	c.487A>C	p.Ser163Arg	missense_variant	Exon 6 of 7		XP_047294750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN4	ENST00000648319.1	c.1159A>C	p.Ser387Arg	missense_variant	Exon 8 of 9		NM_002250.3	ENSP00000496939.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

KCNN4-related disorder Uncertain:1

Jan 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KCNN4 c.1159A>C variant is predicted to result in the amino acid substitution p.Ser387Arg. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;T;T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.76	T;.;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Pathogenic	1.4	D
MutationAssessor	Benign	1.7	.;L;.;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	.;.;.;N
REVEL	Uncertain	0.34
Sift	Benign	0.18	.;.;.;T
Sift4G	Uncertain	0.0090	D;.;T;T
Polyphen		0.36	.;B;.;B
Vest4		0.20, 0.21
MutPred		0.31		.;Gain of catalytic residue at S387 (P = 0.0121);.;Gain of catalytic residue at S387 (P = 0.0121);
MVP		0.89
MPC		0.86
ClinPred		0.086	T
GERP RS		-0.16
Varity_R		0.25
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1466617448; hg19: chr19-44271820;