chr1-154869723-GGCTGCT-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_002249.6(KCNN3):​c.236_241delAGCAGC​(p.Gln79_Gln80del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,504,596 control chromosomes in the GnomAD database, including 42 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.012 ( 36 hom., cov: 0)
Exomes 𝑓: 0.0022 ( 6 hom. )

Consequence

KCNN3
NM_002249.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

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

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-GGCTGCT-G is Benign according to our data. Variant chr1-154869723-GGCTGCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1685389. Variant chr1-154869723-GGCTGCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1685389. Variant chr1-154869723-GGCTGCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1685389. Variant chr1-154869723-GGCTGCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1685389. Variant chr1-154869723-GGCTGCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1685389.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1767/141370) while in subpopulation AFR AF = 0.0411 (1553/37824). AF 95% confidence interval is 0.0394. There are 36 homozygotes in GnomAd4. There are 805 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 36 Unknown,AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNN3NM_002249.6 linkc.236_241delAGCAGC p.Gln79_Gln80del disruptive_inframe_deletion Exon 1 of 8 ENST00000271915.9 NP_002240.3 Q9UGI6-1
KCNN3NM_001204087.2 linkc.236_241delAGCAGC p.Gln79_Gln80del disruptive_inframe_deletion Exon 1 of 9 NP_001191016.1 Q9UGI6A0A087WYJ0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNN3ENST00000271915.9 linkc.236_241delAGCAGC p.Gln79_Gln80del disruptive_inframe_deletion Exon 1 of 8 1 NM_002249.6 ENSP00000271915.3 Q9UGI6-1

Frequencies

GnomAD3 genomes
AF:
0.0125
AC:
1765
AN:
141268
Hom.:
36
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.0411
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00743
Gnomad ASJ
AF:
0.00474
Gnomad EAS
AF:
0.00130
Gnomad SAS
AF:
0.00321
Gnomad FIN
AF:
0.000548
Gnomad MID
AF:
0.0199
Gnomad NFE
AF:
0.000706
Gnomad OTH
AF:
0.00903
GnomAD4 exome
AF:
0.00219
AC:
2982
AN:
1363226
Hom.:
6
AF XY:
0.00217
AC XY:
1465
AN XY:
673940
show subpopulations
African (AFR)
AF:
0.0427
AC:
1326
AN:
31032
American (AMR)
AF:
0.00403
AC:
143
AN:
35492
Ashkenazi Jewish (ASJ)
AF:
0.00473
AC:
118
AN:
24934
East Asian (EAS)
AF:
0.00101
AC:
36
AN:
35566
South Asian (SAS)
AF:
0.00419
AC:
329
AN:
78600
European-Finnish (FIN)
AF:
0.000347
AC:
16
AN:
46050
Middle Eastern (MID)
AF:
0.00678
AC:
30
AN:
4426
European-Non Finnish (NFE)
AF:
0.000728
AC:
765
AN:
1050424
Other (OTH)
AF:
0.00386
AC:
219
AN:
56702
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
111
221
332
442
553
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
62
124
186
248
310
<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:
0.0125
AC:
1767
AN:
141370
Hom.:
36
Cov.:
0
AF XY:
0.0118
AC XY:
805
AN XY:
68002
show subpopulations
African (AFR)
AF:
0.0411
AC:
1553
AN:
37824
American (AMR)
AF:
0.00742
AC:
105
AN:
14156
Ashkenazi Jewish (ASJ)
AF:
0.00474
AC:
16
AN:
3376
East Asian (EAS)
AF:
0.00130
AC:
6
AN:
4614
South Asian (SAS)
AF:
0.00322
AC:
13
AN:
4042
European-Finnish (FIN)
AF:
0.000548
AC:
5
AN:
9120
Middle Eastern (MID)
AF:
0.0213
AC:
6
AN:
282
European-Non Finnish (NFE)
AF:
0.000706
AC:
46
AN:
65184
Other (OTH)
AF:
0.00894
AC:
17
AN:
1902
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
75
149
224
298
373
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.00
Hom.:
292

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Zimmermann-Laband syndrome 3 Uncertain:1
Jul 23, 2020
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

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
=185/15
polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs3831942; hg19: chr1-154842199; COSMIC: COSV55212034; COSMIC: COSV55212034; API