rs1496389

Variant names:

• chr5-114389974-A-G
• rs1496389
• NM_021614.4:c.1219-14464A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021614.4(KCNN2):​c.1219-14464A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 152,022 control chromosomes in the GnomAD database, including 7,115 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7115 hom., cov: 32)
• Consequence: KCNN2 NM_021614.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 1 publications found

Genes affected

KCNN2 (HGNC:6291): (potassium calcium-activated channel subfamily N member 2) 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. This gene is a member of the KCNN family of potassium channel genes. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. Alternate splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

KCNN2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with or without variable movement or behavioral abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN2	NM_021614.4	c.1219-14464A>G		intron_variant	Intron 2 of 7	ENST00000673685.1	NP_067627.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN2	ENST00000673685.1	c.1219-14464A>G		intron_variant	Intron 2 of 7		NM_021614.4	ENSP00000501239.1
KCNN2	ENST00000512097.10	c.1417-14464A>G		intron_variant	Intron 7 of 12	5		ENSP00000427120.4
KCNN2	ENST00000631899.2	c.619-14464A>G		intron_variant	Intron 2 of 8	5		ENSP00000487849.2
KCNN2	ENST00000507750.5	n.249+25973A>G		intron_variant	Intron 2 of 6	3		ENSP00000516687.1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45526 AN: 151904 Hom.: 7102 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.333

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.300 AC: 45573 AN: 152022 Hom.: 7115 Cov.: 32 AF XY: 0.296 AC XY: 22017 AN XY: 74340

African (AFR) AF: 0.226 AC: 9373 AN: 41482

American (AMR) AF: 0.325 AC: 4958 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 911 AN: 3468

East Asian (EAS) AF: 0.123 AC: 637 AN: 5180

South Asian (SAS) AF: 0.287 AC: 1383 AN: 4822

European-Finnish (FIN) AF: 0.310 AC: 3281 AN: 10580

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23796 AN: 67902

Other (OTH) AF: 0.334 AC: 704 AN: 2110

Alfa AF: 0.325 Hom.: 10992

Bravo AF: 0.297

Asia WGS AF: 0.273 AC: 952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.5
DANN	Benign	0.68
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs1496389; hg19: chr5-113725671;