NM_002249.6:c.1449-9142G>A

Variant names:

• chr1-154742286-C-T
• rs11264254
• NM_002249.6:c.1449-9142G>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.1449-9142G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 152,120 control chromosomes in the GnomAD database, including 9,790 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 0.35 (9790 hom., cov: 33)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.756
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.562 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.1449-9142G>A		intron	N/A	NP_002240.3
	KCNN3	NM_001204087.2		c.1449-5198G>A		intron	N/A	NP_001191016.1
	KCNN3	NM_001365837.1		c.510-5198G>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.1449-9142G>A		intron	N/A	ENSP00000271915.3
	KCNN3	ENST00000361147.8	TSL:1	c.534-9142G>A		intron	N/A	ENSP00000354764.4
	KCNN3	ENST00000358505.2	TSL:1	c.510-9142G>A		intron	N/A	ENSP00000351295.2

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52495 AN: 152002 Hom.: 9782 Cov.: 33

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.579

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.346

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

GnomAD4 genome AF: 0.345 AC: 52536 AN: 152120 Hom.: 9790 Cov.: 33 AF XY: 0.349 AC XY: 25920 AN XY: 74360

African (AFR) AF: 0.235 AC: 9770 AN: 41524

American (AMR) AF: 0.375 AC: 5741 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1034 AN: 3472

East Asian (EAS) AF: 0.579 AC: 2990 AN: 5164

South Asian (SAS) AF: 0.388 AC: 1876 AN: 4830

European-Finnish (FIN) AF: 0.397 AC: 4198 AN: 10564

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.378 AC: 25695 AN: 67964

Other (OTH) AF: 0.351 AC: 739 AN: 2108

Alfa AF: 0.345 Hom.: 1386

Bravo AF: 0.341

Asia WGS AF: 0.486 AC: 1692 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.9
DANN	Benign	0.68
PhyloP100		0.76
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: rs11264254; hg19: chr1-154714762;