rs895252839

Variant names:

• chr19-17988433-C-T
• rs895252839
• NM_001386974.1:c.1078C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001386974.1(KCNN1):​c.1078C>T​(p.Leu360Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,612,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: KCNN1 NM_001386974.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85
• Publications: 0 publications found

Genes affected

KCNN1 (HGNC:6290): (potassium calcium-activated channel subfamily N member 1) Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. The protein encoded by this gene is activated before membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. This gene is a member of the KCNN family of potassium channel genes. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386974.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN1	NM_001386974.1	MANE Select	c.1078C>T	p.Leu360Phe	missense	Exon 6 of 10	NP_001373903.1	Q92952-1
	KCNN1	NM_001386975.1		c.1087C>T	p.Leu363Phe	missense	Exon 7 of 11	NP_001373904.1	A0A804HIW7
	KCNN1	NM_001386976.1		c.1087C>T	p.Leu363Phe	missense	Exon 8 of 12	NP_001373905.1	A0A804HIW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN1	ENST00000684775.1	MANE Select	c.1078C>T	p.Leu360Phe	missense	Exon 6 of 10	ENSP00000507021.1	Q92952-1
	KCNN1	ENST00000222249.13	TSL:1	c.1078C>T	p.Leu360Phe	missense	Exon 7 of 11	ENSP00000476519.1	Q92952-1
	KCNN1	ENST00000682733.1		c.1087C>T	p.Leu363Phe	missense	Exon 8 of 12	ENSP00000507255.1	A0A804HIW7

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248270 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460674 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 726536

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111620

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000580 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.9
PrimateAI	Pathogenic	0.83	D
REVEL	Benign	0.25
Sift4G	Uncertain	0.0040	D
Polyphen		0.53	P
Vest4		0.88
MVP		0.77
MPC		3.0
ClinPred		0.93	D
GERP RS		3.6
Varity_R		0.33
gMVP		0.97
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs895252839; hg19: chr19-18099242;