chr1-154707091-C-T

Variant names:

• chr1-154707091-C-T
• rs1995662
• NM_002249.6:c.*885G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000271915.9(KCNN3):​c.*885G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.87 in 152,196 control chromosomes in the GnomAD database, including 57,950 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 0.87 (57949 hom., cov: 32)
  • Exomes 𝑓: 0.75 (1 hom.)
• Consequence: KCNN3 ENST00000271915.9 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 7 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=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000271915.9. 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.*885G>A		3_prime_UTR	Exon 8 of 8	NP_002240.3
	KCNN3	NM_001204087.2		c.*885G>A		3_prime_UTR	Exon 9 of 9	NP_001191016.1
	KCNN3	NM_001365837.1		c.*885G>A		3_prime_UTR	Exon 9 of 9	NP_001352766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	ENST00000271915.9	TSL:1 MANE Select	c.*885G>A		3_prime_UTR	Exon 8 of 8	ENSP00000271915.3
	KCNN3	ENST00000618040.4	TSL:5	c.*885G>A		3_prime_UTR	Exon 9 of 9	ENSP00000481848.1
	KCNN3	ENST00000515643.1	TSL:3	n.305+585G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132302 AN: 152074 Hom.: 57914 Cov.: 32

Gnomad AFR AF: 0.763

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.906

Gnomad ASJ AF: 0.924

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.901

Gnomad OTH AF: 0.884

GnomAD4 exome AF: 0.750 AC: 3 AN: 4 Hom.: 1 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.750 AC: 3 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.870 AC: 132392 AN: 152192 Hom.: 57949 Cov.: 32 AF XY: 0.873 AC XY: 64991 AN XY: 74408

African (AFR) AF: 0.763 AC: 31629 AN: 41480

American (AMR) AF: 0.906 AC: 13853 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.924 AC: 3205 AN: 3470

East Asian (EAS) AF: 0.973 AC: 5041 AN: 5182

South Asian (SAS) AF: 0.947 AC: 4566 AN: 4824

European-Finnish (FIN) AF: 0.927 AC: 9831 AN: 10606

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.901 AC: 61312 AN: 68018

Other (OTH) AF: 0.883 AC: 1869 AN: 2116

Alfa AF: 0.898 Hom.: 38555

Bravo AF: 0.864

Asia WGS AF: 0.933 AC: 3244 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.0
DANN	Benign	0.64
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: rs1995662; hg19: chr1-154679567;