rs1218568

Variant names:

• chr1-154844532-C-T
• rs1218568
• NM_002249.6:c.934-22348G>A

Variant summary

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

The NM_002249.6(KCNN3):​c.934-22348G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 152,100 control chromosomes in the GnomAD database, including 20,038 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 0.49 (20038 hom., cov: 33)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.25
• Publications: 4 publications found

Genes affected

KCNN3 (HGNC:6292): (potassium calcium-activated channel subfamily N member 3) 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. This gene belongs to the KCNN family of potassium channels. It encodes an integral membrane protein that forms a voltage-independent calcium-activated channel, which is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. This gene contains two CAG repeat regions in the coding sequence. It was thought that expansion of one or both of these repeats could lead to an increased susceptibility to schizophrenia or bipolar disorder, but studies indicate that this is probably not the case. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

KCNN3 Gene-Disease associations (from GenCC):

• Zimmermann-Laband syndrome 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Zimmermann-Laband syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002249.6. 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
	KCNN3	NM_002249.6	MANE Select	c.934-22348G>A		intron	N/A	NP_002240.3
	KCNN3	NM_001204087.2		c.934-22348G>A		intron	N/A	NP_001191016.1	A0A087WYJ0
	KCNN3	NM_001365837.1		c.-6-22348G>A		intron	N/A	NP_001352766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	ENST00000271915.9	TSL:1 MANE Select	c.934-22348G>A		intron	N/A	ENSP00000271915.3	Q9UGI6-1
	KCNN3	ENST00000361147.8	TSL:1	c.18+15163G>A		intron	N/A	ENSP00000354764.4	Q9UGI6-2
	KCNN3	ENST00000358505.2	TSL:1	c.-6-22348G>A		intron	N/A	ENSP00000351295.2	Q9UGI6-3

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74905 AN: 151982 Hom.: 20037 Cov.: 33

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.523

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

GnomAD4 genome AF: 0.493 AC: 74918 AN: 152100 Hom.: 20038 Cov.: 33 AF XY: 0.499 AC XY: 37146 AN XY: 74368

African (AFR) AF: 0.294 AC: 12203 AN: 41482

American (AMR) AF: 0.651 AC: 9961 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 2047 AN: 3472

East Asian (EAS) AF: 0.909 AC: 4702 AN: 5170

South Asian (SAS) AF: 0.597 AC: 2876 AN: 4818

European-Finnish (FIN) AF: 0.522 AC: 5514 AN: 10570

Middle Eastern (MID) AF: 0.562 AC: 164 AN: 292

European-Non Finnish (NFE) AF: 0.527 AC: 35835 AN: 67980

Other (OTH) AF: 0.518 AC: 1094 AN: 2112

Alfa AF: 0.486 Hom.: 2465

Bravo AF: 0.498

Asia WGS AF: 0.675 AC: 2349 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.20
DANN	Benign	0.55
PhyloP100		-2.3
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: rs1218568; hg19: chr1-154817008;