5-114362471-C-CCTG

Variant names:

• chr5-114362471-C-CCTG
• rs567706065
• NM_021614.4:c.350_352dupGCT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_Supporting BS1_Supporting BS2

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 (★). Synonymous variant affecting the same amino acid position (i.e. S118S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (22 hom., cov: 33)
  • Exomes 𝑓: 0.012 (15 hom.)
• Consequence: KCNN2 NM_021614.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with or without variable movement or behavioral abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2211 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021614.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN2	NM_021614.4	MANE Select	c.350_352dupGCT	p.Cys117dup	disruptive_inframe_insertion	Exon 1 of 8	NP_067627.3
	KCNN2	NM_001372233.1		c.548_550dupGCT	p.Cys183dup	disruptive_inframe_insertion	Exon 6 of 13	NP_001359162.1	A0A3F2YNY5
	KCNN2	NR_174097.1		n.420_422dupGCT		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN2	ENST00000673685.1	MANE Select	c.350_352dupGCT	p.Cys117dup	disruptive_inframe_insertion	Exon 1 of 8	ENSP00000501239.1	A0A669KBH3
	KCNN2	ENST00000512097.10	TSL:5	c.548_550dupGCT	p.Cys183dup	disruptive_inframe_insertion	Exon 6 of 13	ENSP00000427120.4	A0A3F2YNY5

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2208 AN: 152074 Hom.: 22 Cov.: 33

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.: 15 Cov.: 0 AF XY: 0.0120 AC XY: 1822 AN XY: 151908

African (AFR) AF: 0.0127 AC: 83 AN: 6514

American (AMR) AF: 0.00485 AC: 37 AN: 7632

Ashkenazi Jewish (ASJ) AF: 0.00292 AC: 28 AN: 9600

East Asian (EAS) AF: 0.0000984 AC: 2 AN: 20332

South Asian (SAS) AF: 0.00280 AC: 56 AN: 20002

European-Finnish (FIN) AF: 0.0200 AC: 464 AN: 23198

Middle Eastern (MID) AF: 0.00415 AC: 6 AN: 1446

European-Non Finnish (NFE) AF: 0.0146 AC: 2703 AN: 185124

Other (OTH) AF: 0.0122 AC: 222 AN: 18246

GnomAD4 genome AF: 0.0145 AC: 2211 AN: 152178 Hom.: 22 Cov.: 33 AF XY: 0.0142 AC XY: 1054 AN XY: 74392

African (AFR) AF: 0.0163 AC: 677 AN: 41574

American (AMR) AF: 0.00595 AC: 91 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5164

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4832

European-Finnish (FIN) AF: 0.0204 AC: 216 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0172 AC: 1166 AN: 67956

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00589 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodevelopmental disorder with or without variable movement or behavioral abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=297/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs567706065; hg19: chr5-113698168;