rs1984285

Variant names:

• chr1-154824419-T-G
• rs1984285
• NM_002249.6:c.934-2235A>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.934-2235A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 152,118 control chromosomes in the GnomAD database, including 3,817 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 (3817 hom., cov: 32)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.364
• Publications: 6 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002249.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	NM_002249.6	MANE Select	c.934-2235A>C		intron	N/A	NP_002240.3
	KCNN3	NM_001204087.2		c.934-2235A>C		intron	N/A	NP_001191016.1
	KCNN3	NM_001365837.1		c.-6-2235A>C		intron	N/A	NP_001352766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	ENST00000271915.9	TSL:1 MANE Select	c.934-2235A>C		intron	N/A	ENSP00000271915.3
	KCNN3	ENST00000361147.8	TSL:1	c.19-2235A>C		intron	N/A	ENSP00000354764.4
	KCNN3	ENST00000358505.2	TSL:1	c.-6-2235A>C		intron	N/A	ENSP00000351295.2

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31706 AN: 151998 Hom.: 3814 Cov.: 32

Gnomad AFR AF: 0.0969

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.214

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

GnomAD4 genome AF: 0.208 AC: 31712 AN: 152118 Hom.: 3817 Cov.: 32 AF XY: 0.212 AC XY: 15761 AN XY: 74358

African (AFR) AF: 0.0969 AC: 4020 AN: 41504

American (AMR) AF: 0.302 AC: 4614 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 781 AN: 3470

East Asian (EAS) AF: 0.337 AC: 1742 AN: 5176

South Asian (SAS) AF: 0.199 AC: 959 AN: 4822

European-Finnish (FIN) AF: 0.301 AC: 3186 AN: 10582

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15749 AN: 67948

Other (OTH) AF: 0.213 AC: 449 AN: 2108

Alfa AF: 0.228 Hom.: 7717

Bravo AF: 0.205

Asia WGS AF: 0.252 AC: 874 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.1
DANN	Benign	0.35
PhyloP100		-0.36
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: rs1984285; hg19: chr1-154796895;