1-154860591-C-G

Variant names:

• chr1-154860591-C-G
• rs1218584
• NM_002249.6:c.933+8441G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002249.6(KCNN3):​c.933+8441G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,164 control chromosomes in the GnomAD database, including 3,787 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (3787 hom., cov: 32)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.116
• Publications: 7 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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.933+8441G>C		intron_variant	Intron 1 of 7	ENST00000271915.9	NP_002240.3
KCNN3	NM_001204087.2	c.933+8441G>C		intron_variant	Intron 1 of 8		NP_001191016.1
KCNN3	NM_001365837.1	c.-7+7358G>C		intron_variant	Intron 1 of 8		NP_001352766.1
KCNN3	NM_001365838.1	c.-7+7358G>C		intron_variant	Intron 1 of 7		NP_001352767.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.933+8441G>C		intron_variant	Intron 1 of 7	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000358505.2	c.-7+7358G>C		intron_variant	Intron 1 of 7	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.933+8441G>C		intron_variant	Intron 1 of 8	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32971 AN: 152046 Hom.: 3787 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.00808

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.212

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.217 AC: 32979 AN: 152164 Hom.: 3787 Cov.: 32 AF XY: 0.209 AC XY: 15568 AN XY: 74412

African (AFR) AF: 0.233 AC: 9680 AN: 41506

American (AMR) AF: 0.173 AC: 2639 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 943 AN: 3468

East Asian (EAS) AF: 0.00810 AC: 42 AN: 5186

South Asian (SAS) AF: 0.136 AC: 656 AN: 4826

European-Finnish (FIN) AF: 0.201 AC: 2133 AN: 10594

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16038 AN: 67978

Other (OTH) AF: 0.210 AC: 443 AN: 2112

Alfa AF: 0.137 Hom.: 264

Bravo AF: 0.214

Asia WGS AF: 0.0660 AC: 235 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.1
DANN	Benign	0.48
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1218584; hg19: chr1-154833067;