chr1-154728930-C-T

Variant names:

• chr1-154728930-C-T
• rs12402320
• NM_002249.6:c.1591-2904G>A

Variant summary

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

The NM_002249.6(KCNN3):​c.1591-2904G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 152,040 control chromosomes in the GnomAD database, including 5,708 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 0.27 (5708 hom., cov: 31)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.794
• Publications: 1 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 (NFE) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.1591-2904G>A		intron_variant	Intron 4 of 7	ENST00000271915.9	NP_002240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.1591-2904G>A		intron_variant	Intron 4 of 7	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.676-2904G>A		intron_variant	Intron 4 of 7	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.652-2904G>A		intron_variant	Intron 4 of 7	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.1636-2904G>A		intron_variant	Intron 5 of 8	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40607 AN: 151922 Hom.: 5700 Cov.: 31

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.269

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

GnomAD4 genome AF: 0.267 AC: 40643 AN: 152040 Hom.: 5708 Cov.: 31 AF XY: 0.266 AC XY: 19752 AN XY: 74306

African (AFR) AF: 0.212 AC: 8785 AN: 41478

American (AMR) AF: 0.261 AC: 3982 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 993 AN: 3468

East Asian (EAS) AF: 0.183 AC: 949 AN: 5176

South Asian (SAS) AF: 0.142 AC: 686 AN: 4816

European-Finnish (FIN) AF: 0.372 AC: 3927 AN: 10548

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20485 AN: 67960

Other (OTH) AF: 0.270 AC: 569 AN: 2108

Alfa AF: 0.282 Hom.: 11363

Bravo AF: 0.257

Asia WGS AF: 0.152 AC: 529 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	0.41
DANN	Benign	0.51
PhyloP100		-0.79
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: rs12402320; hg19: chr1-154701406;