chr5-114340308-C-G

Variant names:

• chr5-114340308-C-G
• rs1976311
• NM_001372233.1:c.-184-20637C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001372233.1(KCNN2):​c.-184-20637C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 152,194 control chromosomes in the GnomAD database, including 25 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 0.015 (25 hom., cov: 32)
• Consequence: KCNN2 NM_001372233.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.232
• Publications: 2 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=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.015 (2289/152194) while in subpopulation NFE AF = 0.0225 (1529/68016). AF 95% confidence interval is 0.0215. There are 25 homozygotes in GnomAd4. There are 1134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2289 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN2	NM_001372233.1	c.-184-20637C>G		intron_variant	Intron 4 of 12		NP_001359162.1
KCNN2	XM_011543389.2	c.-184-20637C>G		intron_variant	Intron 3 of 11		XP_011541691.1
KCNN2	XM_047417166.1	c.-1027-20637C>G		intron_variant	Intron 4 of 11		XP_047273122.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN2	ENST00000512097.10	c.-184-20637C>G		intron_variant	Intron 4 of 12	5		ENSP00000427120.4

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2290 AN: 152076 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00787

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00581

Gnomad FIN AF: 0.0344

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0225

Gnomad OTH AF: 0.0143

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

GnomAD4 genome AF: 0.0150 AC: 2289 AN: 152194 Hom.: 25 Cov.: 32 AF XY: 0.0152 AC XY: 1134 AN XY: 74408

African (AFR) AF: 0.00342 AC: 142 AN: 41534

American (AMR) AF: 0.00786 AC: 120 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4818

European-Finnish (FIN) AF: 0.0344 AC: 364 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0225 AC: 1529 AN: 68016

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.0212 Hom.: 8

Bravo AF: 0.0127

Asia WGS AF: 0.00492 AC: 19 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.8
DANN	Benign	0.57
PhyloP100		0.23

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1976311; hg19: chr5-113676005;