1-154731249-G-A

Variant names:

• chr1-154731249-G-A
• rs884664
• NM_002249.6:c.1590+1754C>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.1590+1754C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 152,106 control chromosomes in the GnomAD database, including 7,139 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 0.30 (7139 hom., cov: 33)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.321
• 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=-0.55).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.1590+1754C>T		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.1590+1754C>T		intron_variant	Intron 4 of 7	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.675+1754C>T		intron_variant	Intron 4 of 7	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.651+1754C>T		intron_variant	Intron 4 of 7	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.1635+1754C>T		intron_variant	Intron 5 of 8	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45584 AN: 151988 Hom.: 7133 Cov.: 33

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.299

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

GnomAD4 genome AF: 0.300 AC: 45619 AN: 152106 Hom.: 7139 Cov.: 33 AF XY: 0.304 AC XY: 22613 AN XY: 74336

African (AFR) AF: 0.279 AC: 11570 AN: 41486

American (AMR) AF: 0.394 AC: 6020 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 774 AN: 3464

East Asian (EAS) AF: 0.345 AC: 1785 AN: 5170

South Asian (SAS) AF: 0.455 AC: 2195 AN: 4828

European-Finnish (FIN) AF: 0.257 AC: 2718 AN: 10562

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.288 AC: 19602 AN: 67982

Other (OTH) AF: 0.296 AC: 626 AN: 2112

Alfa AF: 0.292 Hom.: 7732

Bravo AF: 0.310

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.5
DANN	Benign	0.76
PhyloP100		0.32
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: rs884664; hg19: chr1-154703725;