chr1-154869723-G-GGCTGCTGCTGCTGCTGCT

Variant names:

• chr1-154869723-G-GGCTGCTGCTGCTGCTGCT
• rs3831942
• NM_002249.6:c.224_241dupAGCAGCAGCAGCAGCAGC

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.224_241dupAGCAGCAGCAGCAGCAGC​(p.Gln75_Gln80dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (982 hom., cov: 0)
  • Exomes 𝑓: 0.11 (5229 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNN3 NM_002249.6 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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-G-GGCTGCTGCTGCTGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 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.224_241dupAGCAGCAGCAGCAGCAGC	p.Gln75_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	NP_002240.3
	KCNN3	NM_001204087.2		c.224_241dupAGCAGCAGCAGCAGCAGC	p.Gln75_Gln80dup	conservative_inframe_insertion	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.224_241dupAGCAGCAGCAGCAGCAGC	p.Gln75_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000271915.3
	KCNN3	ENST00000618040.4	TSL:5	c.224_241dupAGCAGCAGCAGCAGCAGC	p.Gln75_Gln80dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000481848.1
	ENSG00000308854	ENST00000836873.1		n.195-634_195-617dupCTGCTGCTGCTGCTGCTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.107 AC: 15040 AN: 141088 Hom.: 980 Cov.: 0

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.126

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.115

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.115 AC: 155573 AN: 1355056 Hom.: 5229 Cov.: 112 AF XY: 0.115 AC XY: 77156 AN XY: 669964

African (AFR) AF: 0.0615 AC: 1904 AN: 30962

American (AMR) AF: 0.116 AC: 4082 AN: 35234

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2624 AN: 24788

East Asian (EAS) AF: 0.174 AC: 6172 AN: 35468

South Asian (SAS) AF: 0.136 AC: 10599 AN: 78150

European-Finnish (FIN) AF: 0.118 AC: 5443 AN: 45950

Middle Eastern (MID) AF: 0.133 AC: 587 AN: 4408

European-Non Finnish (NFE) AF: 0.112 AC: 117247 AN: 1043720

Other (OTH) AF: 0.123 AC: 6915 AN: 56376

GnomAD4 genome AF: 0.107 AC: 15044 AN: 141190 Hom.: 982 Cov.: 0 AF XY: 0.108 AC XY: 7304 AN XY: 67922

African (AFR) AF: 0.0676 AC: 2556 AN: 37784

American (AMR) AF: 0.118 AC: 1661 AN: 14126

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 359 AN: 3372

East Asian (EAS) AF: 0.202 AC: 930 AN: 4608

South Asian (SAS) AF: 0.143 AC: 576 AN: 4038

European-Finnish (FIN) AF: 0.129 AC: 1173 AN: 9110

Middle Eastern (MID) AF: 0.121 AC: 34 AN: 282

European-Non Finnish (NFE) AF: 0.114 AC: 7442 AN: 65102

Other (OTH) AF: 0.116 AC: 220 AN: 1900

Alfa AF: 0.112 Hom.: 292

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

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

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.

Zimmermann-Laband syndrome 3 Benign:1

Dec 12, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

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

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: COSV55212934; COSMIC: COSV55212934;