NM_002249.6:c.221_241dupAGCAGCAGCAGCAGCAGCAGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_002249.6(KCNN3):c.221_241dupAGCAGCAGCAGCAGCAGCAGC(p.Gln74_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 Benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 262 hom., cov: 0)

Exomes 𝑓: 0.056 ( 2497 hom. )

Failed GnomAD Quality Control

Consequence

KCNN3
NM_002249.6 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

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: Benign. The variant received -16 ACMG points.

BP6

Variant 1-154869723-G-GGCTGCTGCTGCTGCTGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1685432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1685432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1685432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1685432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1685432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6 link	c.221_241dupAGCAGCAGCAGCAGCAGCAGC	p.Gln74_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	ENST00000271915.9	NP_002240.3	Q9UGI6-1
KCNN3	NM_001204087.2 link	c.221_241dupAGCAGCAGCAGCAGCAGCAGC	p.Gln74_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.221_241dupAGCAGCAGCAGCAGCAGCAGC	p.Gln74_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	1	NM_002249.6	ENSP00000271915.3		Q9UGI6-1

Frequencies

GnomAD3 genomes

AF:

0.0491

AC:

6935

AN:

141176

Hom.:

261

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0407

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.0326

Gnomad ASJ

AF:

0.0264

Gnomad EAS

AF:

0.0493

Gnomad SAS

AF:

0.0383

Gnomad FIN

AF:

0.0314

Gnomad MID

AF:

0.0298

Gnomad NFE

AF:

0.0602

Gnomad OTH

AF:

0.0515

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0562

AC:

76400

AN:

1358946

Hom.:

2497

Cov.:

112

AF XY:

0.0554

AC XY:

37211

AN XY:

671666

show subpopulations

African (AFR)

AF:

0.0426

AC:

1319

AN:

30998

American (AMR)

AF:

0.0308

AC:

1090

AN:

35384

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

758

AN:

24880

East Asian (EAS)

AF:

0.0369

AC:

1310

AN:

35526

South Asian (SAS)

AF:

0.0399

AC:

3135

AN:

78498

European-Finnish (FIN)

AF:

0.0324

AC:

1493

AN:

46084

Middle Eastern (MID)

AF:

0.0287

AC:

127

AN:

4422

European-Non Finnish (NFE)

AF:

0.0614

AC:

64292

AN:

1046574

Other (OTH)

AF:

0.0508

AC:

2876

AN:

56580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

2792

5584

8376

11168

13960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2370

4740

7110

9480

11850

<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:

0.0492

AC:

6951

AN:

141278

Hom.:

262

Cov.:

AF XY:

0.0473

AC XY:

3212

AN XY:

67962

show subpopulations

African (AFR)

AF:

0.0410

AC:

1551

AN:

37814

American (AMR)

AF:

0.0325

AC:

460

AN:

14150

Ashkenazi Jewish (ASJ)

AF:

0.0264

AC:

AN:

3376

East Asian (EAS)

AF:

0.0493

AC:

227

AN:

4608

South Asian (SAS)

AF:

0.0381

AC:

154

AN:

4040

European-Finnish (FIN)

AF:

0.0314

AC:

286

AN:

9116

Middle Eastern (MID)

AF:

0.0319

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0601

AC:

3917

AN:

65124

Other (OTH)

AF:

0.0521

AC:

AN:

1902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

283

566

848

1131

1414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0535

Hom.:

292

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KCNN3-related disorder

Benign:1

Mar 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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