1-154869723-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_002249.6(KCNN3):c.233_241dupAGCAGCAGC(p.Gln78_Gln80dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.13 ( 1519 hom., cov: 0)

Exomes 𝑓: 0.12 ( 2021 hom. )

Failed GnomAD Quality Control

Consequence

KCNN3
NM_002249.6 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

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 -9 ACMG points.

BP6

Variant 1-154869723-G-GGCTGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCTGCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 403006. Variant chr1-154869723-G-GGCTGCTGCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 403006. Variant chr1-154869723-G-GGCTGCTGCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 403006. Variant chr1-154869723-G-GGCTGCTGCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 403006. Variant chr1-154869723-G-GGCTGCTGCT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 403006.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6 link	c.233_241dupAGCAGCAGC	p.Gln78_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	ENST00000271915.9	NP_002240.3	Q9UGI6-1
KCNN3	NM_001204087.2 link	c.233_241dupAGCAGCAGC	p.Gln78_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.233_241dupAGCAGCAGC	p.Gln78_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	1	NM_002249.6	ENSP00000271915.3		Q9UGI6-1

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

18884

AN:

140982

Hom.:

1518

Cov.:

show subpopulations

Gnomad AFR

AF:

0.209

Gnomad AMI

AF:

0.0747

Gnomad AMR

AF:

0.0819

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.0112

Gnomad SAS

AF:

0.132

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.185

Gnomad NFE

AF:

0.113

Gnomad OTH

AF:

0.126

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.119

AC:

156714

AN:

1321026

Hom.:

2021

Cov.:

112

AF XY:

0.119

AC XY:

77685

AN XY:

653388

show subpopulations

African (AFR)

AF:

0.207

AC:

6223

AN:

30048

American (AMR)

AF:

0.0673

AC:

2342

AN:

34824

Ashkenazi Jewish (ASJ)

AF:

0.112

AC:

2745

AN:

24480

East Asian (EAS)

AF:

0.0183

AC:

634

AN:

34556

South Asian (SAS)

AF:

0.137

AC:

10512

AN:

76820

European-Finnish (FIN)

AF:

0.139

AC:

6080

AN:

43720

Middle Eastern (MID)

AF:

0.136

AC:

598

AN:

4382

European-Non Finnish (NFE)

AF:

0.119

AC:

121378

AN:

1017072

Other (OTH)

AF:

0.113

AC:

6202

AN:

55124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

6273

12546

18818

25091

31364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4718

9436

14154

18872

23590

<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:

0.134

AC:

18902

AN:

141082

Hom.:

1519

Cov.:

AF XY:

0.135

AC XY:

9167

AN XY:

67870

show subpopulations

African (AFR)

AF:

0.209

AC:

7891

AN:

37720

American (AMR)

AF:

0.0816

AC:

1154

AN:

14138

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

341

AN:

3372

East Asian (EAS)

AF:

0.0113

AC:

AN:

4614

South Asian (SAS)

AF:

0.133

AC:

536

AN:

4034

European-Finnish (FIN)

AF:

0.137

AC:

1238

AN:

9054

Middle Eastern (MID)

AF:

0.181

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.113

AC:

7334

AN:

65098

Other (OTH)

AF:

0.126

AC:

240

AN:

1900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

697

1393

2090

2786

3483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

214

428

642

856

1070

<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:

0.126

Hom.:

292

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not present in ESP. LOF is NOT an established disease mechanism. Not enough evidence that the gene is associated with cardiomyopathy. Mice homozygous for a conditional gene switch displayed no overt phenotype. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

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 (auto)

(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