NM_002249.6:c.1030-13553G>A

Variant names:

• chr1-154785946-C-T
• rs883319
• NM_002249.6:c.1030-13553G>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.1030-13553G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 152,018 control chromosomes in the GnomAD database, including 3,157 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 0.20 (3157 hom., cov: 32)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.474
• Publications: 13 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 (SAS) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.1030-13553G>A		intron_variant	Intron 2 of 7	ENST00000271915.9	NP_002240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.1030-13553G>A		intron_variant	Intron 2 of 7	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.115-13553G>A		intron_variant	Intron 2 of 7	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.91-13553G>A		intron_variant	Intron 2 of 7	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.1030-13553G>A		intron_variant	Intron 2 of 8	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30557 AN: 151902 Hom.: 3153 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.201

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

GnomAD4 genome AF: 0.201 AC: 30562 AN: 152018 Hom.: 3157 Cov.: 32 AF XY: 0.201 AC XY: 14938 AN XY: 74302

African (AFR) AF: 0.160 AC: 6643 AN: 41474

American (AMR) AF: 0.219 AC: 3347 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 613 AN: 3464

East Asian (EAS) AF: 0.204 AC: 1053 AN: 5174

South Asian (SAS) AF: 0.245 AC: 1182 AN: 4818

European-Finnish (FIN) AF: 0.195 AC: 2055 AN: 10554

Middle Eastern (MID) AF: 0.247 AC: 72 AN: 292

European-Non Finnish (NFE) AF: 0.220 AC: 14982 AN: 67964

Other (OTH) AF: 0.201 AC: 425 AN: 2112

Alfa AF: 0.213 Hom.: 10992

Bravo AF: 0.201

Asia WGS AF: 0.198 AC: 689 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.36
PhyloP100		-0.47
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: rs883319; hg19: chr1-154758422;