rs1218586

Variant names:

• chr1-154859846-A-C
• rs1218586
• NM_002249.6:c.933+9186T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-154859846-A-C
• chr1-154859846-A-G
• chr1-154859846-A-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+9186T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 1,600,466 control chromosomes in the GnomAD database, including 748,599 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 0.96 (69930 hom., cov: 34)
  • Exomes 𝑓: 0.97 (678669 hom.)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191
• Publications: 11 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.933+9186T>G		intron_variant	Intron 1 of 7	ENST00000271915.9	NP_002240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.933+9186T>G		intron_variant	Intron 1 of 7	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000358505.2	c.-7+8103T>G		intron_variant	Intron 1 of 7	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.933+9186T>G		intron_variant	Intron 1 of 8	5		ENSP00000481848.1
KCNN3	ENST00000361147.8	c.-134T>G		upstream_gene_variant		1		ENSP00000354764.4

Frequencies

GnomAD3 genomes AF: 0.958 AC: 145801 AN: 152210 Hom.: 69876 Cov.: 34

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.959

Gnomad AMR AF: 0.961

Gnomad ASJ AF: 0.945

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.986

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.969

Gnomad OTH AF: 0.952

GnomAD4 exome AF: 0.968 AC: 1401869 AN: 1448138 Hom.: 678669 Cov.: 33 AF XY: 0.967 AC XY: 695903 AN XY: 719650

African (AFR) AF: 0.921 AC: 30599 AN: 33216

American (AMR) AF: 0.975 AC: 41962 AN: 43048

Ashkenazi Jewish (ASJ) AF: 0.949 AC: 24522 AN: 25830

East Asian (EAS) AF: 1.00 AC: 39452 AN: 39458

South Asian (SAS) AF: 0.948 AC: 80440 AN: 84872

European-Finnish (FIN) AF: 0.985 AC: 51043 AN: 51834

Middle Eastern (MID) AF: 0.920 AC: 5235 AN: 5688

European-Non Finnish (NFE) AF: 0.970 AC: 1070963 AN: 1104266

Other (OTH) AF: 0.962 AC: 57653 AN: 59926

GnomAD4 genome AF: 0.958 AC: 145914 AN: 152328 Hom.: 69930 Cov.: 34 AF XY: 0.959 AC XY: 71450 AN XY: 74492

African (AFR) AF: 0.929 AC: 38600 AN: 41562

American (AMR) AF: 0.961 AC: 14715 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.945 AC: 3282 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5191 AN: 5194

South Asian (SAS) AF: 0.948 AC: 4577 AN: 4830

European-Finnish (FIN) AF: 0.986 AC: 10468 AN: 10622

Middle Eastern (MID) AF: 0.911 AC: 266 AN: 292

European-Non Finnish (NFE) AF: 0.969 AC: 65931 AN: 68026

Other (OTH) AF: 0.952 AC: 2013 AN: 2114

Alfa AF: 0.962 Hom.: 42422

Bravo AF: 0.954

Asia WGS AF: 0.976 AC: 3395 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	12
DANN	Benign	0.82
PhyloP100		-0.19
PromoterAI		0.012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1218586; hg19: chr1-154832322;