1-154862435-G-A

Variant names:

• chr1-154862435-G-A
• rs6699080
• NM_002249.6:c.933+6597C>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.933+6597C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 151,934 control chromosomes in the GnomAD database, including 16,607 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 0.45 (16607 hom., cov: 31)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.249
• Publications: 15 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.933+6597C>T		intron_variant	Intron 1 of 7	ENST00000271915.9	NP_002240.3
KCNN3	NM_001204087.2	c.933+6597C>T		intron_variant	Intron 1 of 8		NP_001191016.1
KCNN3	NM_001365837.1	c.-7+5514C>T		intron_variant	Intron 1 of 8		NP_001352766.1
KCNN3	NM_001365838.1	c.-7+5514C>T		intron_variant	Intron 1 of 7		NP_001352767.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.933+6597C>T		intron_variant	Intron 1 of 7	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000358505.2	c.-7+5514C>T		intron_variant	Intron 1 of 7	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.933+6597C>T		intron_variant	Intron 1 of 8	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68702 AN: 151816 Hom.: 16595 Cov.: 31

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.452

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

GnomAD4 genome AF: 0.453 AC: 68755 AN: 151934 Hom.: 16607 Cov.: 31 AF XY: 0.460 AC XY: 34128 AN XY: 74266

African (AFR) AF: 0.463 AC: 19153 AN: 41410

American (AMR) AF: 0.547 AC: 8362 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1544 AN: 3462

East Asian (EAS) AF: 0.909 AC: 4683 AN: 5154

South Asian (SAS) AF: 0.616 AC: 2967 AN: 4816

European-Finnish (FIN) AF: 0.387 AC: 4086 AN: 10566

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26586 AN: 67930

Other (OTH) AF: 0.449 AC: 946 AN: 2108

Alfa AF: 0.403 Hom.: 5963

Bravo AF: 0.465

Asia WGS AF: 0.732 AC: 2541 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.31
PhyloP100		0.25
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: rs6699080; hg19: chr1-154834911;