NM_002249.6:c.1448+15057G>A

Variant names:

• chr1-154756918-C-T
• rs10908435
• NM_002249.6:c.1448+15057G>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.1448+15057G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 151,976 control chromosomes in the GnomAD database, including 10,598 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 0.36 (10598 hom., cov: 31)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.127
• Publications: 5 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=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.438 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.1448+15057G>A		intron	N/A	NP_002240.3
	KCNN3	NM_001204087.2		c.1448+15057G>A		intron	N/A	NP_001191016.1
	KCNN3	NM_001365837.1		c.509+15057G>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.1448+15057G>A		intron	N/A	ENSP00000271915.3
	KCNN3	ENST00000361147.8	TSL:1	c.533+15057G>A		intron	N/A	ENSP00000354764.4
	KCNN3	ENST00000358505.2	TSL:1	c.509+15057G>A		intron	N/A	ENSP00000351295.2

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54805 AN: 151858 Hom.: 10594 Cov.: 31

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.378

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

GnomAD4 genome AF: 0.361 AC: 54839 AN: 151976 Hom.: 10598 Cov.: 31 AF XY: 0.357 AC XY: 26550 AN XY: 74268

African (AFR) AF: 0.242 AC: 10025 AN: 41426

American (AMR) AF: 0.337 AC: 5152 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1066 AN: 3464

East Asian (EAS) AF: 0.199 AC: 1028 AN: 5168

South Asian (SAS) AF: 0.353 AC: 1704 AN: 4824

European-Finnish (FIN) AF: 0.417 AC: 4391 AN: 10538

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.442 AC: 30075 AN: 67982

Other (OTH) AF: 0.384 AC: 808 AN: 2106

Alfa AF: 0.419 Hom.: 28233

Bravo AF: 0.350

Asia WGS AF: 0.294 AC: 1026 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.7
DANN	Benign	0.36
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10908435; hg19: chr1-154729394;