1-154869723-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

• chr1-154869723-G-GGCTGCT
• rs3831942
• NM_002249.6:c.236_241dupAGCAGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002249.6(KCNN3):​c.236_241dupAGCAGC​(p.Gln79_Gln80dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0329 in 1,492,684 control chromosomes in the GnomAD database, including 309 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (88 hom., cov: 0)
  • Exomes 𝑓: 0.033 (221 hom.)
• Consequence: KCNN3 NM_002249.6 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• 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 -16 ACMG points.

• BP6: Variant 1-154869723-G-GGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCT is described in CliVar as Benign/Likely_benign. Clinvar id is 682032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCT is described in CliVar as Benign/Likely_benign. Clinvar id is 682032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCT is described in CliVar as Benign/Likely_benign. Clinvar id is 682032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCT is described in CliVar as Benign/Likely_benign. Clinvar id is 682032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCT is described in CliVar as Benign/Likely_benign. Clinvar id is 682032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0304 (4302/141312) while in subpopulation NFE AF = 0.0358 (2331/65150). AF 95% confidence interval is 0.0346. There are 88 homozygotes in GnomAd4. There are 2033 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 88 Unknown,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.236_241dupAGCAGC	p.Gln79_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	ENST00000271915.9	NP_002240.3
KCNN3	NM_001204087.2	c.236_241dupAGCAGC	p.Gln79_Gln80dup	conservative_inframe_insertion	Exon 1 of 9		NP_001191016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.236_241dupAGCAGC	p.Gln79_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	1	NM_002249.6	ENSP00000271915.3

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4302 AN: 141210 Hom.: 88 Cov.: 0

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0265

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.00951

Gnomad SAS AF: 0.0148

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.0298

Gnomad NFE AF: 0.0358

Gnomad OTH AF: 0.0367

GnomAD4 exome AF: 0.0332 AC: 44866 AN: 1351372 Hom.: 221 Cov.: 112 AF XY: 0.0328 AC XY: 21927 AN XY: 667946

African (AFR) AF: 0.0287 AC: 861 AN: 30044

American (AMR) AF: 0.0201 AC: 710 AN: 35364

Ashkenazi Jewish (ASJ) AF: 0.0310 AC: 766 AN: 24736

East Asian (EAS) AF: 0.0121 AC: 430 AN: 35550

South Asian (SAS) AF: 0.0166 AC: 1281 AN: 77382

European-Finnish (FIN) AF: 0.0313 AC: 1430 AN: 45624

Middle Eastern (MID) AF: 0.0446 AC: 195 AN: 4370

European-Non Finnish (NFE) AF: 0.0359 AC: 37411 AN: 1042056

Other (OTH) AF: 0.0317 AC: 1782 AN: 56246

GnomAD4 genome AF: 0.0304 AC: 4302 AN: 141312 Hom.: 88 Cov.: 0 AF XY: 0.0299 AC XY: 2033 AN XY: 67976

African (AFR) AF: 0.0265 AC: 1004 AN: 37826

American (AMR) AF: 0.0264 AC: 374 AN: 14148

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 79 AN: 3374

East Asian (EAS) AF: 0.00910 AC: 42 AN: 4614

South Asian (SAS) AF: 0.0149 AC: 60 AN: 4038

European-Finnish (FIN) AF: 0.0300 AC: 273 AN: 9108

Middle Eastern (MID) AF: 0.0284 AC: 8 AN: 282

European-Non Finnish (NFE) AF: 0.0358 AC: 2331 AN: 65150

Other (OTH) AF: 0.0363 AC: 69 AN: 1902

Alfa AF: 0.0395 Hom.: 292

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Esophageal atresia;C0034194:Pyloric stenosis Uncertain:1

May 22, 2019

Clinical Genetics, Erasmus University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

KCNN3-related disorder Benign:1

Jun 14, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Apr 10, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=75/25	polymorphism

Splicing

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: COSV55212850; COSMIC: COSV55212850;