chr1-154719612-T-C

Variant names:

• chr1-154719612-T-C
• rs4845663
• NM_002249.6:c.1702-4609A>G

Variant summary

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

The NM_001204087.2(KCNN3):​c.1747-4609A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 151,982 control chromosomes in the GnomAD database, including 22,986 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 0.52 (22986 hom., cov: 31)
• Consequence: KCNN3 NM_001204087.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 9 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 (AFR) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204087.2. 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.1702-4609A>G		intron	N/A	NP_002240.3
	KCNN3	NM_001204087.2		c.1747-4609A>G		intron	N/A	NP_001191016.1
	KCNN3	NM_001365837.1		c.808-4609A>G		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.1702-4609A>G		intron	N/A	ENSP00000271915.3
	KCNN3	ENST00000361147.8	TSL:1	c.787-4609A>G		intron	N/A	ENSP00000354764.4
	KCNN3	ENST00000358505.2	TSL:1	c.763-4609A>G		intron	N/A	ENSP00000351295.2

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78313 AN: 151864 Hom.: 22941 Cov.: 31

Gnomad AFR AF: 0.821

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.516 AC: 78417 AN: 151982 Hom.: 22986 Cov.: 31 AF XY: 0.508 AC XY: 37765 AN XY: 74272

African (AFR) AF: 0.821 AC: 34020 AN: 41446

American (AMR) AF: 0.408 AC: 6241 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1421 AN: 3468

East Asian (EAS) AF: 0.277 AC: 1427 AN: 5154

South Asian (SAS) AF: 0.407 AC: 1959 AN: 4814

European-Finnish (FIN) AF: 0.376 AC: 3975 AN: 10574

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27799 AN: 67934

Other (OTH) AF: 0.460 AC: 968 AN: 2106

Alfa AF: 0.441 Hom.: 29749

Bravo AF: 0.530

Asia WGS AF: 0.412 AC: 1437 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.29
DANN	Benign	0.59
PhyloP100		-1.1
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: rs4845663; hg19: chr1-154692088;