chr1-154869723-G-GGCTGCT

Position:

• chr1-154869723-G-GGCTGCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002249.6(KCNN3):​c.241_242insAGCAGC​(p.Gln79_Gln80dup) variant causes a 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 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• 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-GGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCT is described in ClinVar as [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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4302 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNN3	NM_002249.6	c.241_242insAGCAGC	p.Gln79_Gln80dup	inframe_insertion	1/8	ENST00000271915.9
KCNN3	NM_001204087.2	c.241_242insAGCAGC	p.Gln79_Gln80dup	inframe_insertion	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNN3	ENST00000271915.9	c.241_242insAGCAGC	p.Gln79_Gln80dup	inframe_insertion	1/8	1	NM_002249.6	P1
KCNN3	ENST00000618040.4	c.241_242insAGCAGC	p.Gln79_Gln80dup	inframe_insertion	1/9	5

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

Gnomad4 AFR exome AF: 0.0287

Gnomad4 AMR exome AF: 0.0201

Gnomad4 ASJ exome AF: 0.0310

Gnomad4 EAS exome AF: 0.0121

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.0313

Gnomad4 NFE exome AF: 0.0359

Gnomad4 OTH exome AF: 0.0317

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

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.0264

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.00910

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.0300

Gnomad4 NFE AF: 0.0358

Gnomad4 OTH AF: 0.0363

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Esophageal atresia;C0034194:Pyloric stenosis Uncertain:1

Uncertain significance, no assertion criteria provided

research

Clinical Genetics, Erasmus University Medical Center

May 22, 2019

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

KCNN3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2023

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

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. -

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;