Genetic Variant KCNN2:p.Tyr143_Gln146del (chr5-114362558-GGCAGCAGTACGC-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4BS2

The NM_021614.4(KCNN2):c.428_439delACGCGCAGCAGT(p.Tyr143_Gln146del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000391 in 460,938 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

KCNN2
NM_021614.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.06

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: Likely_benign. The variant received -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021614.4.

BS2

High AC in GnomAdExome4 at 18 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.428_439delACGCGCAGCAGT	p.Tyr143_Gln146del	disruptive_inframe_deletion	Exon 1 of 8	NP_067627.3
KCNN2	NM_001372233.1		c.626_637delACGCGCAGCAGT	p.Tyr209_Gln212del	disruptive_inframe_deletion	Exon 6 of 13	NP_001359162.1	A0A3F2YNY5
KCNN2	NR_174097.1		n.498_509delACGCGCAGCAGT		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.428_439delACGCGCAGCAGT	p.Tyr143_Gln146del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000501239.1	A0A669KBH3
KCNN2	ENST00000512097.10	TSL:5	c.626_637delACGCGCAGCAGT	p.Tyr209_Gln212del	disruptive_inframe_deletion	Exon 6 of 13	ENSP00000427120.4	A0A3F2YNY5
KCNN2	ENST00000631899.2	TSL:5	c.-181_-170delGCAGCAGTACGC		upstream_gene	N/A	ENSP00000487849.2	A0A0J9YW81

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000391

AC:

AN:

460938

Hom.:

AF XY:

0.0000292

AC XY:

AN XY:

239774

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9132

American (AMR)

AF:

0.00

AC:

AN:

11790

Ashkenazi Jewish (ASJ)

AF:

0.0000800

AC:

AN:

12504

East Asian (EAS)

AF:

0.00

AC:

AN:

25990

South Asian (SAS)

AF:

0.000266

AC:

AN:

37528

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1956

European-Non Finnish (NFE)

AF:

0.0000228

AC:

AN:

307260

Other (OTH)

AF:

0.00

AC:

AN:

25704

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.1

Mutation Taster

=290/10

polymorphism

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over