rs1218602

Variant names:

• chr1-154818846-G-C
• rs1218602
• NM_002249.6:c.1029+3243C>G

Variant summary

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

The NM_002249.6(KCNN3):​c.1029+3243C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,234 control chromosomes in the GnomAD database, including 4,083 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 0.21 (4083 hom., cov: 33)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.612
• Publications: 2 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 (SAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.1029+3243C>G		intron_variant	Intron 2 of 7	ENST00000271915.9	NP_002240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.1029+3243C>G		intron_variant	Intron 2 of 7	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.114+3243C>G		intron_variant	Intron 2 of 7	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.90+3243C>G		intron_variant	Intron 2 of 7	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.1029+3243C>G		intron_variant	Intron 2 of 8	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32724 AN: 152116 Hom.: 4086 Cov.: 33

Gnomad AFR AF: 0.0987

Gnomad AMI AF: 0.394

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.0812

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.215 AC: 32720 AN: 152234 Hom.: 4083 Cov.: 33 AF XY: 0.218 AC XY: 16229 AN XY: 74430

African (AFR) AF: 0.0985 AC: 4092 AN: 41544

American (AMR) AF: 0.183 AC: 2795 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1156 AN: 3472

East Asian (EAS) AF: 0.0816 AC: 423 AN: 5184

South Asian (SAS) AF: 0.349 AC: 1684 AN: 4826

European-Finnish (FIN) AF: 0.300 AC: 3177 AN: 10598

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18411 AN: 67990

Other (OTH) AF: 0.238 AC: 503 AN: 2110

Alfa AF: 0.249 Hom.: 623

Bravo AF: 0.197

Asia WGS AF: 0.182 AC: 634 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	3.6
DANN	Benign	0.48
PhyloP100		0.61
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: rs1218602; hg19: chr1-154791322;