1-154869723-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

• chr1-154869723-G-GGCTGCTGCTGCT
• rs3831942
• NM_002249.6:c.230_241dupAGCAGCAGCAGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002249.6(KCNN3):​c.230_241dupAGCAGCAGCAGC​(p.Gln77_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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3689 hom., cov: 0)
  • Exomes 𝑓: 0.24 (7801 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNN3 NM_002249.6 conservative_inframe_insertion
• Clinical Significance: 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 -16 ACMG points.

• BP6: Variant 1-154869723-G-GGCTGCTGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 403003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 403003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 403003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 403003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 403003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.230_241dupAGCAGCAGCAGC	p.Gln77_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	ENST00000271915.9	NP_002240.3
KCNN3	NM_001204087.2	c.230_241dupAGCAGCAGCAGC	p.Gln77_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.230_241dupAGCAGCAGCAGC	p.Gln77_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	1	NM_002249.6	ENSP00000271915.3

Frequencies

GnomAD3 genomes AF: 0.221 AC: 31115 AN: 140772 Hom.: 3688 Cov.: 0

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.0733

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.187

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.236 AC: 302058 AN: 1280232 Hom.: 7801 Cov.: 112 AF XY: 0.235 AC XY: 148196 AN XY: 631724

African (AFR) AF: 0.207 AC: 6319 AN: 30558

American (AMR) AF: 0.216 AC: 6286 AN: 29106

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4188 AN: 22034

East Asian (EAS) AF: 0.249 AC: 7281 AN: 29222

South Asian (SAS) AF: 0.189 AC: 13807 AN: 73014

European-Finnish (FIN) AF: 0.267 AC: 11596 AN: 43392

Middle Eastern (MID) AF: 0.137 AC: 572 AN: 4172

European-Non Finnish (NFE) AF: 0.241 AC: 240494 AN: 995872

Other (OTH) AF: 0.218 AC: 11515 AN: 52862

GnomAD4 genome AF: 0.221 AC: 31142 AN: 140870 Hom.: 3689 Cov.: 0 AF XY: 0.222 AC XY: 15036 AN XY: 67734

African (AFR) AF: 0.227 AC: 8583 AN: 37740

American (AMR) AF: 0.169 AC: 2380 AN: 14084

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 506 AN: 3368

East Asian (EAS) AF: 0.179 AC: 826 AN: 4604

South Asian (SAS) AF: 0.174 AC: 701 AN: 4038

European-Finnish (FIN) AF: 0.284 AC: 2557 AN: 9006

Middle Eastern (MID) AF: 0.0786 AC: 22 AN: 280

European-Non Finnish (NFE) AF: 0.231 AC: 14981 AN: 64988

Other (OTH) AF: 0.189 AC: 359 AN: 1896

Alfa AF: 0.248 Hom.: 292

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

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

Nov 25, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: COSV55212152; COSMIC: COSV55212152;