1-154772331-C-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002249.6(KCNN3):​c.1092G>C​(p.Leu364Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,613,672 control chromosomes in the GnomAD database, including 282,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24504 hom., cov: 34)
  • Exomes 𝑓: 0.59 (257612 hom.)
• Consequence: KCNN3 NM_002249.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-154772331-C-G is Benign according to our data. Variant chr1-154772331-C-G is described in ClinVar as [Benign]. Clinvar id is 403001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.146 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85736 AN: 152054 Hom.: 24490 Cov.: 34

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.663

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.704

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.582

GnomAD3 exomes AF: 0.581 AC: 145284 AN: 250190 Hom.: 42601 AF XY: 0.589 AC XY: 79768 AN XY: 135318

Gnomad AFR exome AF: 0.491

Gnomad AMR exome AF: 0.490

Gnomad ASJ exome AF: 0.668

Gnomad EAS exome AF: 0.515

Gnomad SAS exome AF: 0.656

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.598

Gnomad OTH exome AF: 0.585

GnomAD4 exome AF: 0.592 AC: 865456 AN: 1461500 Hom.: 257612 Cov.: 55 AF XY: 0.595 AC XY: 432451 AN XY: 727058

Gnomad4 AFR exome AF: 0.490

Gnomad4 AMR exome AF: 0.488

Gnomad4 ASJ exome AF: 0.660

Gnomad4 EAS exome AF: 0.529

Gnomad4 SAS exome AF: 0.656

Gnomad4 FIN exome AF: 0.599

Gnomad4 NFE exome AF: 0.594

Gnomad4 OTH exome AF: 0.592

GnomAD4 genome AF: 0.564 AC: 85787 AN: 152172 Hom.: 24504 Cov.: 34 AF XY: 0.566 AC XY: 42083 AN XY: 74400

Gnomad4 AFR AF: 0.490

Gnomad4 AMR AF: 0.528

Gnomad4 ASJ AF: 0.663

Gnomad4 EAS AF: 0.522

Gnomad4 SAS AF: 0.644

Gnomad4 FIN AF: 0.613

Gnomad4 NFE AF: 0.601

Gnomad4 OTH AF: 0.583

Alfa AF: 0.536 Hom.: 2949

Bravo AF: 0.557

EpiCase AF: 0.614

EpiControl AF: 0.619

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Zimmermann-laband syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.3
DANN	Benign	0.74

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; COSMIC: COSV55222851;