NM_002249.6:c.934-20597G>T

Variant names:

• chr1-154842781-C-A
• rs6426987
• NM_002249.6:c.934-20597G>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.934-20597G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 152,018 control chromosomes in the GnomAD database, including 9,910 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 0.35 (9910 hom., cov: 30)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.223
• Publications: 9 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.934-20597G>T		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.934-20597G>T		intron_variant	Intron 1 of 7	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.18+16914G>T		intron_variant	Intron 1 of 7	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.-6-20597G>T		intron_variant	Intron 1 of 7	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.934-20597G>T		intron_variant	Intron 1 of 8	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52379 AN: 151900 Hom.: 9890 Cov.: 30

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.0332

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.313

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

GnomAD4 genome AF: 0.345 AC: 52451 AN: 152018 Hom.: 9910 Cov.: 30 AF XY: 0.339 AC XY: 25165 AN XY: 74314

African (AFR) AF: 0.479 AC: 19848 AN: 41430

American (AMR) AF: 0.235 AC: 3586 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 793 AN: 3472

East Asian (EAS) AF: 0.0329 AC: 170 AN: 5172

South Asian (SAS) AF: 0.212 AC: 1021 AN: 4814

European-Finnish (FIN) AF: 0.295 AC: 3113 AN: 10566

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22917 AN: 67964

Other (OTH) AF: 0.320 AC: 674 AN: 2108

Alfa AF: 0.334 Hom.: 16013

Bravo AF: 0.343

Asia WGS AF: 0.203 AC: 702 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.5
DANN	Benign	0.70
PhyloP100		0.22
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: rs6426987; hg19: chr1-154815257;