1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_002249.6(KCNN3):c.212_241dupAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC(p.Gln71_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 0.0028 ( 4 hom., cov: 0)

Exomes 𝑓: 0.00048 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

KCNN3
NM_002249.6 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B: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 -6 ACMG points.

BP6

Variant 1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1685494.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1685494.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1685494.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1685494.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-154869723-G-GGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT is described in CliVar as Benign. Clinvar id is 1685494.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 4 Unknown,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNN3	NM_002249.6 link	c.212_241dupAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gln71_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	ENST00000271915.9	NP_002240.3	Q9UGI6-1
KCNN3	NM_001204087.2 link	c.212_241dupAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gln71_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.212_241dupAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC	p.Gln71_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	1	NM_002249.6	ENSP00000271915.3		Q9UGI6-1

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

384

AN:

141268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00666

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000849

Gnomad ASJ

AF:

0.000296

Gnomad EAS

AF:

0.00259

Gnomad SAS

AF:

0.00346

Gnomad FIN

AF:

0.000439

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00133

Gnomad OTH

AF:

0.00159

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000484

AC:

661

AN:

1365104

Hom.:

Cov.:

112

AF XY:

0.000507

AC XY:

342

AN XY:

674866

show subpopulations

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

African (AFR)

AF:

0.00302

AC:

AN:

31104

American (AMR)

AF:

0.000535

AC:

AN:

35514

Ashkenazi Jewish (ASJ)

AF:

0.000160

AC:

AN:

24960

East Asian (EAS)

AF:

0.00163

AC:

AN:

35568

South Asian (SAS)

AF:

0.00100

AC:

AN:

78744

European-Finnish (FIN)

AF:

0.000303

AC:

AN:

46140

Middle Eastern (MID)

AF:

0.000902

AC:

AN:

4434

European-Non Finnish (NFE)

AF:

0.000341

AC:

359

AN:

1051840

Other (OTH)

AF:

0.000528

AC:

AN:

56800

⚠️ 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: 0.359

Heterozygous variant carriers

117

156

195

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:

0.00275

AC:

389

AN:

141370

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

198

AN XY:

68000

show subpopulations

African (AFR)

AF:

0.00677

AC:

256

AN:

37828

American (AMR)

AF:

0.000848

AC:

AN:

14158

Ashkenazi Jewish (ASJ)

AF:

0.000296

AC:

AN:

3376

East Asian (EAS)

AF:

0.00260

AC:

AN:

4612

South Asian (SAS)

AF:

0.00346

AC:

AN:

4042

European-Finnish (FIN)

AF:

0.000439

AC:

AN:

9120

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00133

AC:

AN:

65180

Other (OTH)

AF:

0.00158

AC:

AN:

1902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

May 04, 2022

Mendelics

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

(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