1-154772331-C-T

Variant names:

• chr1-154772331-C-T
• rs1051614
• NM_002249.6:c.1092G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The NM_002249.6(KCNN3):​c.1092G>A​(p.Leu364Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,613,816 control chromosomes in the GnomAD database, including 159 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. Synonymous variant affecting the same amino acid position (i.e. L364L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0091 (11 hom., cov: 34)
  • Exomes 𝑓: 0.013 (148 hom.)
• Consequence: KCNN3 NM_002249.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.146
• Publications: 26 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP7: Synonymous conserved (PhyloP=-0.146 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.013 (18929/1461608) while in subpopulation NFE AF = 0.0153 (16974/1111852). AF 95% confidence interval is 0.0151. There are 148 homozygotes in GnomAdExome4. There are 9375 alleles in the male GnomAdExome4 subpopulation. Median coverage is 55. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 Unknown,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.1092G>A	p.Leu364Leu	synonymous_variant	Exon 3 of 8	ENST00000271915.9	NP_002240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.1092G>A	p.Leu364Leu	synonymous_variant	Exon 3 of 8	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.177G>A	p.Leu59Leu	synonymous_variant	Exon 3 of 8	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.153G>A	p.Leu51Leu	synonymous_variant	Exon 3 of 8	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.1092G>A	p.Leu364Leu	synonymous_variant	Exon 3 of 9	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.00907 AC: 1380 AN: 152090 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00985 AC: 2465 AN: 250190 AF XY: 0.00984

Gnomad AFR exome AF: 0.00217

Gnomad AMR exome AF: 0.00616

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0130 AC: 18929 AN: 1461608 Hom.: 148 Cov.: 55 AF XY: 0.0129 AC XY: 9375 AN XY: 727104

African (AFR) AF: 0.00134 AC: 45 AN: 33480

American (AMR) AF: 0.00616 AC: 275 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00327 AC: 282 AN: 86250

European-Finnish (FIN) AF: 0.0126 AC: 673 AN: 53376

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0153 AC: 16974 AN: 1111852

Other (OTH) AF: 0.00985 AC: 595 AN: 60390

GnomAD4 genome AF: 0.00906 AC: 1379 AN: 152208 Hom.: 11 Cov.: 34 AF XY: 0.00868 AC XY: 646 AN XY: 74416

African (AFR) AF: 0.00210 AC: 87 AN: 41520

American (AMR) AF: 0.00699 AC: 107 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.0114 AC: 121 AN: 10600

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0149 AC: 1015 AN: 67998

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00899 Hom.: 2949

EpiCase AF: 0.0127

EpiControl AF: 0.0115

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.3
DANN	Benign	0.89
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism

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: rs1051614; hg19: chr1-154744807;