1-154859828-T-C

Variant names:

• chr1-154859828-T-C
• rs4845397
• ENST00000361147.8:c.-116A>G

Variant summary

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

The ENST00000361147.8(KCNN3):​c.-116A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 1,609,248 control chromosomes in the GnomAD database, including 423,479 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 0.66 (34481 hom., cov: 34)
  • Exomes 𝑓: 0.73 (388998 hom.)
• Consequence: KCNN3 ENST00000361147.8 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 22 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.933+9204A>G		intron_variant	Intron 1 of 7	ENST00000271915.9	NP_002240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.933+9204A>G		intron_variant	Intron 1 of 7	1	NM_002249.6	ENSP00000271915.3

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99787 AN: 152090 Hom.: 34459 Cov.: 34

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.631

Gnomad EAS AF: 0.990

Gnomad SAS AF: 0.807

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.671

GnomAD4 exome AF: 0.727 AC: 1058903 AN: 1457040 Hom.: 388998 Cov.: 35 AF XY: 0.729 AC XY: 528072 AN XY: 724616

African (AFR) AF: 0.424 AC: 14146 AN: 33378

American (AMR) AF: 0.825 AC: 36612 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 17030 AN: 26048

East Asian (EAS) AF: 0.994 AC: 39433 AN: 39660

South Asian (SAS) AF: 0.798 AC: 68533 AN: 85836

European-Finnish (FIN) AF: 0.756 AC: 39940 AN: 52856

Middle Eastern (MID) AF: 0.649 AC: 3726 AN: 5744

European-Non Finnish (NFE) AF: 0.718 AC: 796331 AN: 1108908

Other (OTH) AF: 0.716 AC: 43152 AN: 60238

GnomAD4 genome AF: 0.656 AC: 99858 AN: 152208 Hom.: 34481 Cov.: 34 AF XY: 0.667 AC XY: 49635 AN XY: 74428

African (AFR) AF: 0.440 AC: 18257 AN: 41504

American (AMR) AF: 0.750 AC: 11478 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.631 AC: 2191 AN: 3472

East Asian (EAS) AF: 0.990 AC: 5129 AN: 5182

South Asian (SAS) AF: 0.807 AC: 3895 AN: 4828

European-Finnish (FIN) AF: 0.757 AC: 8035 AN: 10612

Middle Eastern (MID) AF: 0.664 AC: 194 AN: 292

European-Non Finnish (NFE) AF: 0.716 AC: 48714 AN: 67996

Other (OTH) AF: 0.674 AC: 1425 AN: 2114

Alfa AF: 0.701 Hom.: 20108

Bravo AF: 0.648

Asia WGS AF: 0.886 AC: 3077 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.45
DANN	Benign	0.43
PhyloP100		-1.2
PromoterAI		-0.0088	Neutral
Mutation Taster		=86/214	disease causing

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: rs4845397; hg19: chr1-154832304;