5-114362492-C-T

Variant names:

• chr5-114362492-C-T
• rs544525765
• NM_021614.4:c.353C>T

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.353C>T​(p.Ser118Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00033 in 466,008 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 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 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: KCNN2 NM_021614.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87
• 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: Labcorp Genetics (formerly Invitae), G2P

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=0.23983023).
• BS2: High AC in GnomAd4 at 37 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.353C>T	p.Ser118Leu	missense	Exon 1 of 8	NP_067627.3
	KCNN2	NM_001372233.1		c.551C>T	p.Ser184Leu	missense	Exon 6 of 13	NP_001359162.1	A0A3F2YNY5
	KCNN2	NR_174097.1		n.423C>T		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.353C>T	p.Ser118Leu	missense	Exon 1 of 8	ENSP00000501239.1	A0A669KBH3
	KCNN2	ENST00000512097.10	TSL:5	c.551C>T	p.Ser184Leu	missense	Exon 6 of 13	ENSP00000427120.4	A0A3F2YNY5
	KCNN2	ENST00000631899.2	TSL:5	c.-248C>T		upstream_gene	N/A	ENSP00000487849.2	A0A0J9YW81

Frequencies

GnomAD3 genomes AF: 0.000244 AC: 37 AN: 151938 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000373 AC: 117 AN: 313962 Hom.: 1 Cov.: 3 AF XY: 0.000387 AC XY: 63 AN XY: 162846

African (AFR) AF: 0.000290 AC: 2 AN: 6896

American (AMR) AF: 0.00 AC: 0 AN: 8302

Ashkenazi Jewish (ASJ) AF: 0.00379 AC: 39 AN: 10282

East Asian (EAS) AF: 0.0000452 AC: 1 AN: 22116

South Asian (SAS) AF: 0.00110 AC: 23 AN: 20826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24970

Middle Eastern (MID) AF: 0.00194 AC: 3 AN: 1548

European-Non Finnish (NFE) AF: 0.000155 AC: 31 AN: 199510

Other (OTH) AF: 0.000923 AC: 18 AN: 19512

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152046 Hom.: 0 Cov.: 33 AF XY: 0.000283 AC XY: 21 AN XY: 74332

African (AFR) AF: 0.0000723 AC: 3 AN: 41500

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67904

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000246

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Uncertain	0.51
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	0.98
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.24	T
PhyloP100		4.9
GERP RS		5.0
PromoterAI		0.018	Neutral
Mutation Taster		=236/64	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: rs544525765; hg19: chr5-113698189;