chr1-154869723-G-GGCTGCTGCT

Position:

• chr1-154869723-G-GGCTGCTGCT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_002249.6(KCNN3):​c.241_242insAGCAGCAGC​(p.Gln78_Gln80dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1519 hom., cov: 0)
  • Exomes 𝑓: 0.12 (2021 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNN3 NM_002249.6 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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 -9 ACMG points.

• BP6: Variant 1-154869723-G-GGCTGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCTGCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403006.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNN3	NM_002249.6	c.241_242insAGCAGCAGC	p.Gln78_Gln80dup	inframe_insertion	1/8	ENST00000271915.9	NP_002240.3
KCNN3	NM_001204087.2	c.241_242insAGCAGCAGC	p.Gln78_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_242insAGCAGCAGC	p.Gln78_Gln80dup	inframe_insertion	1/8	1	NM_002249.6	ENSP00000271915	P1
KCNN3	ENST00000618040.4	c.241_242insAGCAGCAGC	p.Gln78_Gln80dup	inframe_insertion	1/9	5		ENSP00000481848

Frequencies

GnomAD3 genomes AF: 0.134 AC: 18884 AN: 140982 Hom.: 1518 Cov.: 0

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.126

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.119 AC: 156714 AN: 1321026 Hom.: 2021 Cov.: 112 AF XY: 0.119 AC XY: 77685 AN XY: 653388

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.0673

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.0183

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.134 AC: 18902 AN: 141082 Hom.: 1519 Cov.: 0 AF XY: 0.135 AC XY: 9167 AN XY: 67870

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.0816

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.0113

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.126

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, 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: Not present in ESP. LOF is NOT an established disease mechanism. Not enough evidence that the gene is associated with cardiomyopathy. Mice homozygous for a conditional gene switch displayed no overt phenotype. -

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;