chr1-154869723-GGCT-G

Variant names:

• chr1-154869723-GGCT-G
• rs3831942
• NM_002249.6:c.239_241delAGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002249.6(KCNN3):​c.239_241delAGC​(p.Gln80del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 1,505,328 control chromosomes in the GnomAD database, including 408 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (151 hom., cov: 0)
  • Exomes 𝑓: 0.043 (257 hom.)
• Consequence: KCNN3 NM_002249.6 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.12

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 -16 ACMG points.

• BP6: Variant 1-154869723-GGCT-G is Benign according to our data. Variant chr1-154869723-GGCT-G is described in ClinVar as [Benign]. Clinvar id is 403004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.239_241delAGC	p.Gln80del	disruptive_inframe_deletion	Exon 1 of 8	ENST00000271915.9	NP_002240.3
KCNN3	NM_001204087.2	c.239_241delAGC	p.Gln80del	disruptive_inframe_deletion	Exon 1 of 9		NP_001191016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.239_241delAGC	p.Gln80del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_002249.6	ENSP00000271915.3
KCNN3	ENST00000618040.4	c.239_241delAGC	p.Gln80del	disruptive_inframe_deletion	Exon 1 of 9	5		ENSP00000481848.1

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6409 AN: 141212 Hom.: 151 Cov.: 0

Gnomad AFR AF: 0.0595

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.0353

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.0477

Gnomad MID AF: 0.0364

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0521

GnomAD4 exome AF: 0.0429 AC: 58521 AN: 1364014 Hom.: 257 AF XY: 0.0425 AC XY: 28625 AN XY: 674284

Gnomad4 AFR exome AF: 0.0587

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.0320

Gnomad4 EAS exome AF: 0.00231

Gnomad4 SAS exome AF: 0.0378

Gnomad4 FIN exome AF: 0.0464

Gnomad4 NFE exome AF: 0.0449

Gnomad4 OTH exome AF: 0.0440

GnomAD4 genome AF: 0.0454 AC: 6415 AN: 141314 Hom.: 151 Cov.: 0 AF XY: 0.0450 AC XY: 3058 AN XY: 67988

Gnomad4 AFR AF: 0.0595

Gnomad4 AMR AF: 0.0295

Gnomad4 ASJ AF: 0.0353

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.0384

Gnomad4 FIN AF: 0.0477

Gnomad4 NFE AF: 0.0448

Gnomad4 OTH AF: 0.0515

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 (18 homozygotes in ExAC) -

Computational scores

Source: dbNSFP v4.3

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: rs3831942; hg19: chr1-154842199;