1-154869723-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

• chr1-154869723-G-GGCTGCTGCTGCTGCT
• rs3831942
• NM_002249.6:c.227_241dupAGCAGCAGCAGCAGC

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.227_241dupAGCAGCAGCAGCAGC​(p.Gln76_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 0.30 (7510 hom., cov: 0)
  • Exomes 𝑓: 0.29 (19618 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNN3 NM_002249.6 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts 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-GGCTGCTGCTGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1290509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1290509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1290509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1290509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1290509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.227_241dupAGCAGCAGCAGCAGC	p.Gln76_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	ENST00000271915.9	NP_002240.3
KCNN3	NM_001204087.2	c.227_241dupAGCAGCAGCAGCAGC	p.Gln76_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.227_241dupAGCAGCAGCAGCAGC	p.Gln76_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	1	NM_002249.6	ENSP00000271915.3

Frequencies

GnomAD3 genomes AF: 0.301 AC: 42429 AN: 140906 Hom.: 7505 Cov.: 0

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.324

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.292 AC: 391526 AN: 1341996 Hom.: 19618 Cov.: 112 AF XY: 0.292 AC XY: 193574 AN XY: 663426

African (AFR) AF: 0.116 AC: 3563 AN: 30830

American (AMR) AF: 0.391 AC: 13570 AN: 34664

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 8682 AN: 24474

East Asian (EAS) AF: 0.392 AC: 13571 AN: 34624

South Asian (SAS) AF: 0.282 AC: 21703 AN: 77050

European-Finnish (FIN) AF: 0.265 AC: 12033 AN: 45480

Middle Eastern (MID) AF: 0.287 AC: 1246 AN: 4338

European-Non Finnish (NFE) AF: 0.290 AC: 300494 AN: 1034714

Other (OTH) AF: 0.299 AC: 16664 AN: 55822

GnomAD4 genome AF: 0.301 AC: 42440 AN: 141008 Hom.: 7510 Cov.: 0 AF XY: 0.302 AC XY: 20519 AN XY: 67850

African (AFR) AF: 0.138 AC: 5206 AN: 37788

American (AMR) AF: 0.448 AC: 6326 AN: 14124

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1539 AN: 3372

East Asian (EAS) AF: 0.496 AC: 2275 AN: 4586

South Asian (SAS) AF: 0.330 AC: 1331 AN: 4028

European-Finnish (FIN) AF: 0.300 AC: 2717 AN: 9060

Middle Eastern (MID) AF: 0.351 AC: 99 AN: 282

European-Non Finnish (NFE) AF: 0.341 AC: 22136 AN: 65000

Other (OTH) AF: 0.322 AC: 612 AN: 1900

Alfa AF: 0.335 Hom.: 292

ClinVar

Significance: Benign

Submissions summary: 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

- -

not provided Benign:1

Nov 25, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Zimmermann-Laband syndrome 3 Benign:1

Oct 11, 2021

Fulgent Genetics, Fulgent Genetics

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: COSV55211766; COSMIC: COSV55211766;