1-154718969-C-T

Variant names:

• chr1-154718969-C-T
• rs10128027
• NM_002249.6:c.1702-3966G>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.1702-3966G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 152,066 control chromosomes in the GnomAD database, including 30,829 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 0.63 (30829 hom., cov: 32)
• Consequence: KCNN3 NM_002249.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.751
• Publications: 8 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.1702-3966G>A		intron_variant	Intron 5 of 7	ENST00000271915.9	NP_002240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.1702-3966G>A		intron_variant	Intron 5 of 7	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.787-3966G>A		intron_variant	Intron 5 of 7	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.763-3966G>A		intron_variant	Intron 5 of 7	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.1747-3966G>A		intron_variant	Intron 6 of 8	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95432 AN: 151946 Hom.: 30821 Cov.: 32

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.646

Gnomad EAS AF: 0.787

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.703

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.631

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

GnomAD4 genome AF: 0.628 AC: 95460 AN: 152066 Hom.: 30829 Cov.: 32 AF XY: 0.633 AC XY: 47052 AN XY: 74358

African (AFR) AF: 0.475 AC: 19680 AN: 41444

American (AMR) AF: 0.673 AC: 10294 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 2241 AN: 3470

East Asian (EAS) AF: 0.788 AC: 4082 AN: 5182

South Asian (SAS) AF: 0.710 AC: 3414 AN: 4810

European-Finnish (FIN) AF: 0.703 AC: 7447 AN: 10594

Middle Eastern (MID) AF: 0.586 AC: 171 AN: 292

European-Non Finnish (NFE) AF: 0.680 AC: 46205 AN: 67962

Other (OTH) AF: 0.627 AC: 1325 AN: 2112

Alfa AF: 0.662 Hom.: 113785

Bravo AF: 0.619

Asia WGS AF: 0.699 AC: 2432 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.9
DANN	Benign	0.57
PhyloP100		0.75
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10128027; hg19: chr1-154691445;