rs1131820

Variant names:

• chr1-154772376-A-G
• rs1131820
• NM_002249.6:c.1047T>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.1047T>C​(p.Asn349Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 1,613,634 control chromosomes in the GnomAD database, including 442,919 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39672 hom., cov: 34)
  • Exomes 𝑓: 0.74 (403247 hom.)
• Consequence: KCNN3 NM_002249.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.41

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=-0.56).
• BP6: Variant 1-154772376-A-G is Benign according to our data. Variant chr1-154772376-A-G is described in ClinVar as [Benign]. Clinvar id is 403002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.1047T>C	p.Asn349Asn	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.1047T>C	p.Asn349Asn	synonymous_variant	Exon 3 of 8	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000361147.8	c.132T>C	p.Asn44Asn	synonymous_variant	Exon 3 of 8	1		ENSP00000354764.4
KCNN3	ENST00000358505.2	c.108T>C	p.Asn36Asn	synonymous_variant	Exon 3 of 8	1		ENSP00000351295.2
KCNN3	ENST00000618040.4	c.1047T>C	p.Asn349Asn	synonymous_variant	Exon 3 of 9	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.717 AC: 109036 AN: 152082 Hom.: 39653 Cov.: 34

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.982

Gnomad SAS AF: 0.839

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.738

GnomAD3 exomes AF: 0.769 AC: 192467 AN: 250314 Hom.: 75149 AF XY: 0.768 AC XY: 104026 AN XY: 135402

Gnomad AFR exome AF: 0.615

Gnomad AMR exome AF: 0.877

Gnomad ASJ exome AF: 0.756

Gnomad EAS exome AF: 0.986

Gnomad SAS exome AF: 0.833

Gnomad FIN exome AF: 0.693

Gnomad NFE exome AF: 0.722

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.740 AC: 1081752 AN: 1461434 Hom.: 403247 Cov.: 60 AF XY: 0.743 AC XY: 539901 AN XY: 727010

Gnomad4 AFR exome AF: 0.616

Gnomad4 AMR exome AF: 0.869

Gnomad4 ASJ exome AF: 0.751

Gnomad4 EAS exome AF: 0.984

Gnomad4 SAS exome AF: 0.834

Gnomad4 FIN exome AF: 0.689

Gnomad4 NFE exome AF: 0.724

Gnomad4 OTH exome AF: 0.748

GnomAD4 genome AF: 0.717 AC: 109110 AN: 152200 Hom.: 39672 Cov.: 34 AF XY: 0.722 AC XY: 53715 AN XY: 74404

Gnomad4 AFR AF: 0.618

Gnomad4 AMR AF: 0.819

Gnomad4 ASJ AF: 0.763

Gnomad4 EAS AF: 0.982

Gnomad4 SAS AF: 0.839

Gnomad4 FIN AF: 0.692

Gnomad4 NFE AF: 0.728

Gnomad4 OTH AF: 0.738

Alfa AF: 0.731 Hom.: 65775

Bravo AF: 0.723

Asia WGS AF: 0.874 AC: 3035 AN: 3478

EpiCase AF: 0.737

EpiControl AF: 0.738

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Zimmermann-laband syndrome 3 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.2
DANN	Benign	0.50

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: rs1131820; hg19: chr1-154744852; COSMIC: COSV55222871;