1-154869723-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT-GGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

• chr1-154869723-GGCT-G
• rs3831942
• NM_002249.6:c.239_241delAGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_002249.6(KCNN3):​c.239_241delAGC​(p.Gln80del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 1,505,328 control chromosomes in the GnomAD database, including 408 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (151 hom., cov: 0)
  • Exomes 𝑓: 0.043 (257 hom.)
• Consequence: KCNN3 NM_002249.6 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.12
• Publications: 18 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)

ENSG00000308854 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_002249.6
• BP6: Variant 1-154869723-GGCT-G is Benign according to our data. Variant chr1-154869723-GGCT-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0575 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	NM_002249.6	MANE Select	c.239_241delAGC	p.Gln80del	disruptive_inframe_deletion	Exon 1 of 8	NP_002240.3
	KCNN3	NM_001204087.2		c.239_241delAGC	p.Gln80del	disruptive_inframe_deletion	Exon 1 of 9	NP_001191016.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	ENST00000271915.9	TSL:1 MANE Select	c.239_241delAGC	p.Gln80del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000271915.3
	KCNN3	ENST00000618040.4	TSL:5	c.239_241delAGC	p.Gln80del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000481848.1
	ENSG00000308854	ENST00000836873.1		n.195-619_195-617delCTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6409 AN: 141212 Hom.: 151 Cov.: 0

Gnomad AFR AF: 0.0595

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.0353

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.0477

Gnomad MID AF: 0.0364

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0521

GnomAD4 exome AF: 0.0429 AC: 58521 AN: 1364014 Hom.: 257 AF XY: 0.0425 AC XY: 28625 AN XY: 674284

African (AFR) AF: 0.0587 AC: 1820 AN: 31002

American (AMR) AF: 0.0233 AC: 828 AN: 35470

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 798 AN: 24934

East Asian (EAS) AF: 0.00231 AC: 82 AN: 35568

South Asian (SAS) AF: 0.0378 AC: 2966 AN: 78492

European-Finnish (FIN) AF: 0.0464 AC: 2139 AN: 46122

Middle Eastern (MID) AF: 0.0407 AC: 180 AN: 4422

European-Non Finnish (NFE) AF: 0.0449 AC: 47210 AN: 1051264

Other (OTH) AF: 0.0440 AC: 2498 AN: 56740

GnomAD4 genome AF: 0.0454 AC: 6415 AN: 141314 Hom.: 151 Cov.: 0 AF XY: 0.0450 AC XY: 3058 AN XY: 67988

African (AFR) AF: 0.0595 AC: 2252 AN: 37818

American (AMR) AF: 0.0295 AC: 418 AN: 14156

Ashkenazi Jewish (ASJ) AF: 0.0353 AC: 119 AN: 3372

East Asian (EAS) AF: 0.00173 AC: 8 AN: 4614

South Asian (SAS) AF: 0.0384 AC: 155 AN: 4040

European-Finnish (FIN) AF: 0.0477 AC: 435 AN: 9118

Middle Eastern (MID) AF: 0.0426 AC: 12 AN: 282

European-Non Finnish (NFE) AF: 0.0448 AC: 2918 AN: 65142

Other (OTH) AF: 0.0515 AC: 98 AN: 1902

Alfa AF: 0.0102 Hom.: 292

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency (18 homozygotes in ExAC)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=86/14	polymorphism

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: rs3831942; hg19: chr1-154842199; COSMIC: COSV55217508; COSMIC: COSV55217508;