chr1-154841143-G-A

Variant names:

• chr1-154841143-G-A
• rs6426985
• NM_002249.6:c.934-18959C>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.934-18959C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 152,070 control chromosomes in the GnomAD database, including 14,012 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 0.42 (14012 hom., cov: 32)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 6 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 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.934-18959C>T		intron	N/A	NP_002240.3
	KCNN3	NM_001204087.2		c.934-18959C>T		intron	N/A	NP_001191016.1
	KCNN3	NM_001365837.1		c.-6-18959C>T		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.934-18959C>T		intron	N/A	ENSP00000271915.3
	KCNN3	ENST00000361147.8	TSL:1	c.18+18552C>T		intron	N/A	ENSP00000354764.4
	KCNN3	ENST00000358505.2	TSL:1	c.-6-18959C>T		intron	N/A	ENSP00000351295.2

Frequencies

GnomAD3 genomes AF: 0.421 AC: 64045 AN: 151952 Hom.: 13994 Cov.: 32

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.0441

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.417

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

GnomAD4 genome AF: 0.422 AC: 64114 AN: 152070 Hom.: 14012 Cov.: 32 AF XY: 0.417 AC XY: 31006 AN XY: 74324

African (AFR) AF: 0.474 AC: 19659 AN: 41448

American (AMR) AF: 0.314 AC: 4804 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1372 AN: 3470

East Asian (EAS) AF: 0.0438 AC: 227 AN: 5186

South Asian (SAS) AF: 0.387 AC: 1864 AN: 4820

European-Finnish (FIN) AF: 0.460 AC: 4868 AN: 10574

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.441 AC: 29943 AN: 67966

Other (OTH) AF: 0.423 AC: 891 AN: 2108

Alfa AF: 0.422 Hom.: 5550

Bravo AF: 0.409

Asia WGS AF: 0.285 AC: 987 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.077
DANN	Benign	0.53
PhyloP100		-1.3
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: rs6426985; hg19: chr1-154813619;