Genetic Variant NM_021614.4:c.329C>G (chr5-114362468-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_021614.4(KCNN2):c.329C>G(p.Ser110Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 286,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 6/9 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. S110L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

KCNN2
NM_021614.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.39

Publications

0 publications found

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 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)

KCNN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.24309477).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNN2	NM_021614.4	MANE Select	c.329C>G	p.Ser110Trp	missense	Exon 1 of 8	NP_067627.3
KCNN2	NM_001372233.1		c.527C>G	p.Ser176Trp	missense	Exon 6 of 13	NP_001359162.1	A0A3F2YNY5
KCNN2	NR_174097.1		n.399C>G		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.329C>G	p.Ser110Trp	missense	Exon 1 of 8	ENSP00000501239.1	A0A669KBH3
	KCNN2	ENST00000512097.10	TSL:5	c.527C>G	p.Ser176Trp	missense	Exon 6 of 13	ENSP00000427120.4	A0A3F2YNY5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000349

AC:

AN:

286124

Hom.:

Cov.:

AF XY:

0.00000674

AC XY:

AN XY:

148424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6498

American (AMR)

AF:

0.00

AC:

AN:

7338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9480

East Asian (EAS)

AF:

0.00

AC:

AN:

20002

South Asian (SAS)

AF:

0.00

AC:

AN:

18844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1418

European-Non Finnish (NFE)

AF:

0.00000550

AC:

AN:

181680

Other (OTH)

AF:

0.00

AC:

AN:

18004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Benign

0.92

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.69

MetaRNN

Benign

0.24

PhyloP100

2.4

GERP RS

5.3

PromoterAI

-0.032

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over