rs1218585

Variant names:

• chr1-154860185-G-A
• rs1218585
• NM_002249.6:c.933+8847C>T

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+8847C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,236 control chromosomes in the GnomAD database, including 2,735 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 0.18 (2735 hom., cov: 32)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.577
• Publications: 12 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.933+8847C>T		intron_variant	Intron 1 of 7	ENST00000271915.9	NP_002240.3
KCNN3	NM_001204087.2	c.933+8847C>T		intron_variant	Intron 1 of 8		NP_001191016.1
KCNN3	NM_001365837.1	c.-7+7764C>T		intron_variant	Intron 1 of 8		NP_001352766.1
KCNN3	NM_001365838.1	c.-7+7764C>T		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+8847C>T		intron_variant	Intron 1 of 7	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000358505.2	c.-7+7764C>T		intron_variant	Intron 1 of 7	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.933+8847C>T		intron_variant	Intron 1 of 8	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27113 AN: 152118 Hom.: 2737 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.00924

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.182

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

GnomAD4 genome AF: 0.178 AC: 27114 AN: 152236 Hom.: 2735 Cov.: 32 AF XY: 0.172 AC XY: 12840 AN XY: 74442

African (AFR) AF: 0.119 AC: 4933 AN: 41544

American (AMR) AF: 0.154 AC: 2358 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 924 AN: 3468

East Asian (EAS) AF: 0.00926 AC: 48 AN: 5184

South Asian (SAS) AF: 0.126 AC: 610 AN: 4832

European-Finnish (FIN) AF: 0.198 AC: 2102 AN: 10592

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15370 AN: 67992

Other (OTH) AF: 0.180 AC: 380 AN: 2114

Alfa AF: 0.211 Hom.: 3658

Bravo AF: 0.170

Asia WGS AF: 0.0530 AC: 187 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.83
PhyloP100		-0.58
PromoterAI		-0.033	Neutral
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: rs1218585; hg19: chr1-154832661;