NM_002249.6:c.209_241dupAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP5_ModerateBS2

The NM_002249.6(KCNN3):c.209_241dupAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC(p.Gln70_Gln80dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.00059 ( 2 hom., cov: 0)

Exomes 𝑓: 0.00017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNN3
NM_002249.6 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.12

Publications

18 publications found

Variant links:

Genes affected

KCNN3 (HGNC:6292): (potassium calcium-activated channel subfamily N member 3) 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. This gene belongs to the KCNN family of potassium channels. It encodes an integral membrane protein that forms a voltage-independent calcium-activated channel, which is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. This gene contains two CAG repeat regions in the coding sequence. It was thought that expansion of one or both of these repeats could lead to an increased susceptibility to schizophrenia or bipolar disorder, but studies indicate that this is probably not the case. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

KCNN3 Gene-Disease associations (from GenCC):

Zimmermann-Laband syndrome 3
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Zimmermann-Laband syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
schizophrenia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

KCNN3 links:

ENSG00000308854 (HGNC:):

ENSG00000308854 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP5

Variant 1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is Pathogenic according to our data. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Likely_pathogenic. Clinvar id is 3910119.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Likely_pathogenic. Clinvar id is 3910119.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Likely_pathogenic. Clinvar id is 3910119.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Likely_pathogenic. Clinvar id is 3910119.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Likely_pathogenic. Clinvar id is 3910119.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 Unknown,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6 link	c.209_241dupAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gln70_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	ENST00000271915.9	NP_002240.3	Q9UGI6-1
KCNN3	NM_001204087.2 link	c.209_241dupAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gln70_Gln80dup	conservative_inframe_insertion	Exon 1 of 9		NP_001191016.1	Q9UGI6A0A087WYJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNN3	ENST00000271915.9 link	c.209_241dupAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gln70_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	1	NM_002249.6	ENSP00000271915.3		Q9UGI6-1

Frequencies

GnomAD3 genomes

AF:

0.000595

AC:

AN:

141286

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000424

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00216

Gnomad SAS

AF:

0.00222

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000199

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000173

AC:

236

AN:

1365110

Hom.:

Cov.:

112

AF XY:

0.000207

AC XY:

140

AN XY:

674876

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000482

AC:

AN:

31108

American (AMR)

AF:

0.000225

AC:

AN:

35514

Ashkenazi Jewish (ASJ)

AF:

0.0000401

AC:

AN:

24960

East Asian (EAS)

AF:

0.00160

AC:

AN:

35560

South Asian (SAS)

AF:

0.00117

AC:

AN:

78748

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46140

Middle Eastern (MID)

AF:

0.000226

AC:

AN:

4432

European-Non Finnish (NFE)

AF:

0.0000494

AC:

AN:

1051844

Other (OTH)

AF:

0.000176

AC:

AN:

56804

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.352

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:

0.000594

AC:

AN:

141388

Hom.:

Cov.:

AF XY:

0.000647

AC XY:

AN XY:

68016

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

37840

American (AMR)

AF:

0.000424

AC:

AN:

14158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3376

East Asian (EAS)

AF:

0.00217

AC:

AN:

4614

South Asian (SAS)

AF:

0.00223

AC:

AN:

4042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9120

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000199

AC:

AN:

65184

Other (OTH)

AF:

0.00

AC:

AN:

1902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=75/25

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over