Genetic Variant NM_021614.4:c.350_352dupGCT (chr5-114362471-C-CCTG) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_SupportingBS1_SupportingBS2

The NM_021614.4(KCNN2):c.350_352dupGCT(p.Cys117dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 444,272 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.015 ( 22 hom., cov: 33)

Exomes 𝑓: 0.012 ( 15 hom. )

Consequence

KCNN2
NM_021614.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

Variant links:

Genes affected

KCNN2 (HGNC:6291): (potassium calcium-activated channel subfamily N member 2) 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. The protein encoded by this gene is activated before membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. This gene is a member of the KCNN family of potassium channel genes. The encoded protein is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. Alternate splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

KCNN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021614.4. Strenght limited to Supporting due to length of the change: 1aa.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0145 (2211/152178) while in subpopulation NFE AF= 0.0172 (1166/67956). AF 95% confidence interval is 0.0163. There are 22 homozygotes in gnomad4. There are 1054 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 2211 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN2	NM_021614.4 link	c.350_352dupGCT	p.Cys117dup	disruptive_inframe_insertion	Exon 1 of 8	ENST00000673685.1	NP_067627.3	Q9H2S1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN2	ENST00000673685.1 link	c.350_352dupGCT	p.Cys117dup	disruptive_inframe_insertion	Exon 1 of 8		NM_021614.4	ENSP00000501239.1		A0A669KBH3
KCNN2	ENST00000512097.10 link	c.548_550dupGCT	p.Cys183dup	disruptive_inframe_insertion	Exon 6 of 13	5		ENSP00000427120.4		A0A3F2YNY5

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2208

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00596

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.0204

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0110

GnomAD4 exome

AF:

0.0123

AC:

3601

AN:

292094

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

1822

AN XY:

151908

show subpopulations

Gnomad4 AFR exome

AF:

0.0127

Gnomad4 AMR exome

AF:

0.00485

Gnomad4 ASJ exome

AF:

0.00292

Gnomad4 EAS exome

AF:

0.0000984

Gnomad4 SAS exome

AF:

0.00280

Gnomad4 FIN exome

AF:

0.0200

Gnomad4 NFE exome

AF:

0.0146

Gnomad4 OTH exome

AF:

0.0122

GnomAD4 genome

AF:

0.0145

AC:

2211

AN:

152178

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1054

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0163

Gnomad4 AMR

AF:

0.00595

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0204

Gnomad4 NFE

AF:

0.0172

Gnomad4 OTH

AF:

0.0109

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with or without variable movement or behavioral abnormalities

Uncertain:1

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed inframe insertion variant c.350_352dup(p.Cys117dup) in KCNN2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.350_352dup has 1.7% allele frequency in gnomAD Exomes. This variant p.Cys117dup causes duplication of amino acid Cysteine at postion 117. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over