NM_021614.4:c.520G>C

Variant names:

• chr5-114362659-G-C
• rs1196354188
• NM_021614.4:c.520G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_021614.4(KCNN2):​c.520G>C​(p.Gly174Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,371,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/9 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G174S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KCNN2 NM_021614.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281
• 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 -5 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.2857 (below the threshold of 3.09). Trascript score misZ: 1.564 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with or without variable movement or behavioral abnormalities.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17949948).
• BS2: High AC in GnomAdExome4 at 14 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.520G>C	p.Gly174Arg	missense	Exon 1 of 8	NP_067627.3
	KCNN2	NM_001372233.1		c.718G>C	p.Gly240Arg	missense	Exon 6 of 13	NP_001359162.1	A0A3F2YNY5
	KCNN2	NR_174097.1		n.590G>C		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.520G>C	p.Gly174Arg	missense	Exon 1 of 8	ENSP00000501239.1	A0A669KBH3
	KCNN2	ENST00000512097.10	TSL:5	c.718G>C	p.Gly240Arg	missense	Exon 6 of 13	ENSP00000427120.4	A0A3F2YNY5
	KCNN2	ENST00000631899.2	TSL:5	c.-81G>C		upstream_gene	N/A	ENSP00000487849.2	A0A0J9YW81

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150892 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000115 AC: 14 AN: 1220742 Hom.: 0 Cov.: 20 AF XY: 0.0000134 AC XY: 8 AN XY: 596332

African (AFR) AF: 0.00 AC: 0 AN: 26150

American (AMR) AF: 0.00 AC: 0 AN: 18788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18120

East Asian (EAS) AF: 0.00 AC: 0 AN: 33132

South Asian (SAS) AF: 0.0000163 AC: 1 AN: 61484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4598

European-Non Finnish (NFE) AF: 0.0000133 AC: 13 AN: 976972

Other (OTH) AF: 0.00 AC: 0 AN: 51390

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150892 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73648

African (AFR) AF: 0.00 AC: 0 AN: 41024

American (AMR) AF: 0.00 AC: 0 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 4960

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67664

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Benign	0.74
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.18	T
PhyloP100		0.28
GERP RS		3.9
PromoterAI		0.0042	Neutral
Mutation Taster		=293/7	polymorphism

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

Other links and lift over

dbSNP: rs1196354188; hg19: chr5-113698356;