NM_002249.6:c.1449-14297G>A

Variant names:

• chr1-154747441-C-T
• rs906281
• NM_002249.6:c.1449-14297G>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.1449-14297G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 152,090 control chromosomes in the GnomAD database, including 46,648 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 0.78 (46648 hom., cov: 31)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.33
• Publications: 3 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)

ENSG00000296078 (HGNC:):

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 (EAS) allele frequency at 95% confidence interval = 0.966 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.1449-14297G>A		intron	N/A	NP_002240.3
	KCNN3	NM_001204087.2		c.1449-10353G>A		intron	N/A	NP_001191016.1
	KCNN3	NM_001365837.1		c.510-10353G>A		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.1449-14297G>A		intron	N/A	ENSP00000271915.3
	KCNN3	ENST00000361147.8	TSL:1	c.534-14297G>A		intron	N/A	ENSP00000354764.4
	KCNN3	ENST00000358505.2	TSL:1	c.510-14297G>A		intron	N/A	ENSP00000351295.2

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118559 AN: 151972 Hom.: 46608 Cov.: 31

Gnomad AFR AF: 0.714

Gnomad AMI AF: 0.690

Gnomad AMR AF: 0.850

Gnomad ASJ AF: 0.800

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.802

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.786

Gnomad OTH AF: 0.797

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

GnomAD4 genome AF: 0.780 AC: 118659 AN: 152090 Hom.: 46648 Cov.: 31 AF XY: 0.786 AC XY: 58408 AN XY: 74330

African (AFR) AF: 0.715 AC: 29616 AN: 41446

American (AMR) AF: 0.850 AC: 12999 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.800 AC: 2775 AN: 3470

East Asian (EAS) AF: 0.989 AC: 5116 AN: 5174

South Asian (SAS) AF: 0.801 AC: 3855 AN: 4810

European-Finnish (FIN) AF: 0.785 AC: 8312 AN: 10582

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.786 AC: 53460 AN: 67990

Other (OTH) AF: 0.798 AC: 1688 AN: 2114

Alfa AF: 0.782 Hom.: 72696

Bravo AF: 0.782

Asia WGS AF: 0.890 AC: 3097 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.045
DANN	Benign	0.75
PhyloP100		-2.3
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: rs906281; hg19: chr1-154719917;