chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCT

Position:

• chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCT

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_002249.6(KCNN3):​c.241_242insAGCAGCAGCAGCAGCAGCAGCAGC​(p.Gln73_Gln80dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (15 hom., cov: 0)
  • Exomes 𝑓: 0.0031 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNN3 NM_002249.6 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter 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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCT is described in ClinVar as [Benign]. Clinvar id is 1685406.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 1105 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.241_242insAGCAGCAGCAGCAGCAGCAGCAGC	p.Gln73_Gln80dup	inframe_insertion	1/8	ENST00000271915.9	NP_002240.3
KCNN3	NM_001204087.2	c.241_242insAGCAGCAGCAGCAGCAGCAGCAGC	p.Gln73_Gln80dup	inframe_insertion	1/9		NP_001191016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9	c.241_242insAGCAGCAGCAGCAGCAGCAGCAGC	p.Gln73_Gln80dup	inframe_insertion	1/8	1	NM_002249.6	ENSP00000271915	P1
KCNN3	ENST00000618040.4	c.241_242insAGCAGCAGCAGCAGCAGCAGCAGC	p.Gln73_Gln80dup	inframe_insertion	1/9	5		ENSP00000481848

Frequencies

GnomAD3 genomes AF: 0.00781 AC: 1104 AN: 141268 Hom.: 15 Cov.: 0

Gnomad AFR AF: 0.00753

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00545

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00821

Gnomad SAS AF: 0.00593

Gnomad FIN AF: 0.00219

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00874

Gnomad OTH AF: 0.0122

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00312 AC: 4262 AN: 1364938 Hom.: 0 Cov.: 112 AF XY: 0.00331 AC XY: 2236 AN XY: 674744

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.00287

Gnomad4 ASJ exome AF: 0.0121

Gnomad4 EAS exome AF: 0.0136

Gnomad4 SAS exome AF: 0.00503

Gnomad4 FIN exome AF: 0.00247

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.00428

GnomAD4 genome AF: 0.00782 AC: 1105 AN: 141370 Hom.: 15 Cov.: 0 AF XY: 0.00781 AC XY: 531 AN XY: 68012

Gnomad4 AFR AF: 0.00759

Gnomad4 AMR AF: 0.00544

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00824

Gnomad4 SAS AF: 0.00569

Gnomad4 FIN AF: 0.00219

Gnomad4 NFE AF: 0.00873

Gnomad4 OTH AF: 0.0121

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

KCNN3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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;