1-154772331-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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. gnomad4_exome 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 gnomad4_exome. There are 9375 alleles in male gnomad4_exome subpopulation. Median coverage is 55. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1379 AD 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

GnomAD3 exomes AF: 0.00985 AC: 2465 AN: 250190 Hom.: 21 AF XY: 0.00984 AC XY: 1331 AN XY: 135318

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 SAS exome AF: 0.00307

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

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00616

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00327

Gnomad4 FIN exome AF: 0.0126

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.00985

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

Gnomad4 AFR AF: 0.00210

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.0104

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1051614; hg19: chr1-154744807;