chr1-154869723-G-GGCTGCT

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_002249.6(KCNN3):c.236_241dupAGCAGC(p.Gln79_Gln80dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0329 in 1,492,684 control chromosomes in the GnomAD database, including 309 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 88 hom., cov: 0)

Exomes 𝑓: 0.033 ( 221 hom. )

Consequence

KCNN3
NM_002249.6 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:4

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_002249.6

BP6

Variant 1-154869723-G-GGCTGCT is Benign according to our data. Variant chr1-154869723-G-GGCTGCT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 682032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0304 (4302/141312) while in subpopulation NFE AF = 0.0358 (2331/65150). AF 95% confidence interval is 0.0346. There are 88 homozygotes in GnomAd4. There are 2033 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 88 Unknown,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002249.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNN3	NM_002249.6	MANE Select	c.236_241dupAGCAGC	p.Gln79_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	NP_002240.3
	KCNN3	NM_001204087.2		c.236_241dupAGCAGC	p.Gln79_Gln80dup	conservative_inframe_insertion	Exon 1 of 9	NP_001191016.1	A0A087WYJ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNN3	ENST00000271915.9	TSL:1 MANE Select	c.236_241dupAGCAGC	p.Gln79_Gln80dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000271915.3	Q9UGI6-1
KCNN3	ENST00000618040.4	TSL:5	c.236_241dupAGCAGC	p.Gln79_Gln80dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000481848.1	A0A087WYJ0
KCNN3	ENST00000874071.1		c.236_241dupAGCAGC	p.Gln79_Gln80dup	conservative_inframe_insertion	Exon 1 of 7	ENSP00000544130.1

Frequencies

GnomAD3 genomes

AF:

0.0305

AC:

4302

AN:

141210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0265

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0265

Gnomad ASJ

AF:

0.0234

Gnomad EAS

AF:

0.00951

Gnomad SAS

AF:

0.0148

Gnomad FIN

AF:

0.0300

Gnomad MID

AF:

0.0298

Gnomad NFE

AF:

0.0358

Gnomad OTH

AF:

0.0367

GnomAD4 exome

AF:

0.0332

AC:

44866

AN:

1351372

Hom.:

221

Cov.:

112

AF XY:

0.0328

AC XY:

21927

AN XY:

667946

show subpopulations

African (AFR)

AF:

0.0287

AC:

861

AN:

30044

American (AMR)

AF:

0.0201

AC:

710

AN:

35364

Ashkenazi Jewish (ASJ)

AF:

0.0310

AC:

766

AN:

24736

East Asian (EAS)

AF:

0.0121

AC:

430

AN:

35550

South Asian (SAS)

AF:

0.0166

AC:

1281

AN:

77382

European-Finnish (FIN)

AF:

0.0313

AC:

1430

AN:

45624

Middle Eastern (MID)

AF:

0.0446

AC:

195

AN:

4370

European-Non Finnish (NFE)

AF:

0.0359

AC:

37411

AN:

1042056

Other (OTH)

AF:

0.0317

AC:

1782

AN:

56246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

2130

4261

6391

8522

10652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1412

2824

4236

5648

7060

<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:

0.0304

AC:

4302

AN:

141312

Hom.:

Cov.:

AF XY:

0.0299

AC XY:

2033

AN XY:

67976

show subpopulations

African (AFR)

AF:

0.0265

AC:

1004

AN:

37826

American (AMR)

AF:

0.0264

AC:

374

AN:

14148

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

AN:

3374

East Asian (EAS)

AF:

0.00910

AC:

AN:

4614

South Asian (SAS)

AF:

0.0149

AC:

AN:

4038

European-Finnish (FIN)

AF:

0.0300

AC:

273

AN:

9108

Middle Eastern (MID)

AF:

0.0284

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0358

AC:

2331

AN:

65150

Other (OTH)

AF:

0.0363

AC:

AN:

1902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

188

376

565

753

941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0395

Hom.:

292

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Esophageal atresia;C0034194:Pyloric stenosis (1)

KCNN3-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over