1-154869723-G-GGCTGCTGCTGCTGCTGCT

Position:

• chr1-154869723-G-GGCTGCTGCTGCTGCTGCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002249.6(KCNN3):​c.241_242insAGCAGCAGCAGCAGCAGC​(p.Gln75_Gln80dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. 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 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.12

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-154869723-G-GGCTGCTGCTGCTGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCT is described in ClinVar as [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.241_242insAGCAGCAGCAGCAGCAGC	p.Gln75_Gln80dup	inframe_insertion	1/8	ENST00000271915.9	NP_002240.3
KCNN3	NM_001204087.2	c.241_242insAGCAGCAGCAGCAGCAGC	p.Gln75_Gln80dup	inframe_insertion	1/9		NP_001191016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.241_242insAGCAGCAGCAGCAGCAGC	p.Gln75_Gln80dup	inframe_insertion	1/8	1	NM_002249.6	ENSP00000271915	P1
KCNN3	ENST00000618040.4	c.241_242insAGCAGCAGCAGCAGCAGC	p.Gln75_Gln80dup	inframe_insertion	1/9	5		ENSP00000481848

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

Gnomad4 AFR exome AF: 0.0615

Gnomad4 AMR exome AF: 0.116

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.174

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.123

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

Gnomad4 AFR AF: 0.0676

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 10, 2018

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

Benign, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3831942; hg19: chr1-154842199;