1-154744675-A-G

Variant names:

• chr1-154744675-A-G
• rs11577391
• NM_002249.6:c.1449-11531T>C

Variant summary

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

The NM_001204087.2(KCNN3):​c.1449-7587T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 152,124 control chromosomes in the GnomAD database, including 5,689 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 0.27 (5689 hom., cov: 32)
• Consequence: KCNN3 NM_001204087.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.35
• Publications: 1 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204087.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	NM_002249.6	MANE Select	c.1449-11531T>C		intron	N/A	NP_002240.3
	KCNN3	NM_001204087.2		c.1449-7587T>C		intron	N/A	NP_001191016.1
	KCNN3	NM_001365837.1		c.510-7587T>C		intron	N/A	NP_001352766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	ENST00000271915.9	TSL:1 MANE Select	c.1449-11531T>C		intron	N/A	ENSP00000271915.3
	KCNN3	ENST00000361147.8	TSL:1	c.534-11531T>C		intron	N/A	ENSP00000354764.4
	KCNN3	ENST00000358505.2	TSL:1	c.510-11531T>C		intron	N/A	ENSP00000351295.2

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40864 AN: 152004 Hom.: 5686 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.298

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

GnomAD4 genome AF: 0.269 AC: 40873 AN: 152124 Hom.: 5689 Cov.: 32 AF XY: 0.269 AC XY: 20042 AN XY: 74372

African (AFR) AF: 0.227 AC: 9424 AN: 41494

American (AMR) AF: 0.269 AC: 4112 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1295 AN: 3470

East Asian (EAS) AF: 0.211 AC: 1093 AN: 5180

South Asian (SAS) AF: 0.190 AC: 918 AN: 4822

European-Finnish (FIN) AF: 0.304 AC: 3217 AN: 10568

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19904 AN: 67986

Other (OTH) AF: 0.297 AC: 626 AN: 2106

Alfa AF: 0.275 Hom.: 2050

Bravo AF: 0.264

Asia WGS AF: 0.183 AC: 636 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0050
DANN	Benign	0.55
PhyloP100		-2.4
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: rs11577391; hg19: chr1-154717151;