Genetic Variant KCNN2:p.Ser118Ser (chr5-114362493-G-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_021614.4(KCNN2):c.354G>T(p.Ser118Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000745 in 456,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

KCNN2
NM_021614.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.696

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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 5-114362493-G-T is Benign according to our data. Variant chr5-114362493-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2655643.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.696 with no splicing effect.

BS2

High AC in GnomAd4 at 7 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNN2	NM_021614.4	MANE Select	c.354G>T	p.Ser118Ser	synonymous	Exon 1 of 8	NP_067627.3
KCNN2	NM_001372233.1		c.552G>T	p.Ser184Ser	synonymous	Exon 6 of 13	NP_001359162.1	A0A3F2YNY5
KCNN2	NR_174097.1		n.424G>T		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNN2	ENST00000673685.1	MANE Select	c.354G>T	p.Ser118Ser	synonymous	Exon 1 of 8	ENSP00000501239.1	A0A669KBH3
KCNN2	ENST00000512097.10	TSL:5	c.552G>T	p.Ser184Ser	synonymous	Exon 6 of 13	ENSP00000427120.4	A0A3F2YNY5
KCNN2	ENST00000631899.2	TSL:5	c.-247G>T		upstream_gene	N/A	ENSP00000487849.2	A0A0J9YW81

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000887

AC:

AN:

304300

Hom.:

Cov.:

AF XY:

0.0000698

AC XY:

AN XY:

157540

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6860

American (AMR)

AF:

0.000887

AC:

AN:

7888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10102

East Asian (EAS)

AF:

0.00

AC:

AN:

21794

South Asian (SAS)

AF:

0.00

AC:

AN:

18706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1508

European-Non Finnish (NFE)

AF:

0.0000980

AC:

AN:

193910

Other (OTH)

AF:

0.0000524

AC:

AN:

19078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.000131

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000736

AC:

AN:

67948

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000529

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

9.4

(source)

DANN

Benign

0.95

PhyloP100

0.70

PromoterAI

-0.021

Neutral

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over