1-154737064-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002249.6(KCNN3):c.1449-3920T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00934 in 702,356 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (45 hom.)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.14

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-154737064-A-C is Benign according to our data. Variant chr1-154737064-A-C is described in ClinVar as [Benign]. Clinvar id is 2639378.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00977 (5373/550074) while in subpopulation MID AF= 0.0357 (145/4062). AF 95% confidence interval is 0.031. There are 45 homozygotes in gnomad4_exome. There are 2835 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd at 1189 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNN3	NM_002249.6	c.1449-3920T>G		intron_variant		ENST00000271915.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNN3	ENST00000271915.9	c.1449-3920T>G		intron_variant		1	NM_002249.6	P1
KCNN3	ENST00000358505.2	c.510-3920T>G		intron_variant		1
KCNN3	ENST00000361147.8	c.534-3920T>G		intron_variant		1
KCNN3	ENST00000618040.4	c.1473T>G	p.Ser491=	synonymous_variant	4/9	5

Frequencies

GnomAD3 genomes AF: 0.00781 AC: 1189 AN: 152164 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00833 AC: 1069 AN: 128368 Hom.: 7 AF XY: 0.00824 AC XY: 579 AN XY: 70294

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.00665

Gnomad ASJ exome AF: 0.0274

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00259

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.00977 AC: 5373 AN: 550074 Hom.: 45 Cov.: 0 AF XY: 0.00952 AC XY: 2835 AN XY: 297788

Gnomad4 AFR exome AF: 0.00247

Gnomad4 AMR exome AF: 0.00683

Gnomad4 ASJ exome AF: 0.0283

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00261

Gnomad4 FIN exome AF: 0.00175

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.00779 AC: 1187 AN: 152282 Hom.: 8 Cov.: 32 AF XY: 0.00735 AC XY: 547 AN XY: 74468

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0117 Hom.: 1

Bravo AF: 0.00846

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

KCNN3: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	3.6
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs112506792; hg19: chr1-154709540;