ClinVar Genomic variation as it relates to human health
NM_001099857.5(IKBKG):c.1167dup (p.Glu390fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001099857.5(IKBKG):c.1167dup (p.Glu390fs)
Variation ID: 372387 Accession: VCV000372387.12
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: Xq28 X: 154564361-154564362 (GRCh38) [ NCBI UCSC ] X: 153792576-153792577 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 9, 2017 Apr 15, 2024 Dec 14, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001099857.5:c.1167dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001093327.1:p.Glu390fs frameshift NM_001099856.6:c.1371_1372insC NM_001099856.6:c.1371dup NP_001093326.2:p.Glu458fs frameshift NM_001145255.4:c.870dup NP_001138727.1:p.Glu291fs frameshift NM_001321396.3:c.1167dup NP_001308325.1:p.Glu390fs frameshift NM_001321397.3:c.1164dup NP_001308326.1:p.Glu389fs frameshift NM_001377312.1:c.1167dup NP_001364241.1:p.Glu390fs frameshift NM_001377313.1:c.1164dup NP_001364242.1:p.Glu389fs frameshift NM_001377314.1:c.1011dup NP_001364243.1:p.Glu338fs frameshift NM_001377315.1:c.798dup NP_001364244.1:p.Glu267fs frameshift NM_003639.3:c.1167dupC NM_003639.4:c.1167dup NP_003630.1:p.Glu390fs frameshift NR_165197.1:n.1036dup non-coding transcript variant NC_000023.11:g.154564368dup NC_000023.10:g.153792583dup NG_009896.1:g.27125dup LRG_70:g.27125dup LRG_70t1:c.1167dup - Protein change
- E390fs, E389fs, E291fs, E458fs, E267fs, E338fs
- Other names
- p.(E390Rfs*5)
- Canonical SPDI
- NC_000023.11:154564361:CCCCCCC:CCCCCCCC
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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IKBKG | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
116 | 405 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2001 | RCV000012209.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 14, 2022 | RCV000413717.4 | |
Pathogenic (3) |
criteria provided, single submitter
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- | RCV001172473.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 27, 2021 | RCV002506000.1 | |
Pathogenic (1) |
no assertion criteria provided
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May 10, 2023 | RCV003992285.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490564.4
First in ClinVar: Jan 09, 2017 Last updated: Dec 24, 2022 |
Comment:
Published functional studies demonstrate a damaging effect on protein function (Ohnishi et al., 2017; Kawai et al., 2012); Frameshift variant in the C-terminus predicted to … (more)
Published functional studies demonstrate a damaging effect on protein function (Ohnishi et al., 2017; Kawai et al., 2012); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost and replaced with 4 incorrect amino acids; truncated region removes a portion of the zinc finger domain (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22517901, 18350553, 11484156, 18347290, 30982207, 31713830, 32035679, 34061330, 11047757, 27577878, 18222329, 11179023, 28702714) (less)
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Pathogenic
(Oct 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Ectodermal dysplasia and immunodeficiency 1
Immunodeficiency 33 Incontinentia pigmenti syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809225.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Incontinentia pigmenti syndrome
Affected status: yes
Allele origin:
de novo
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Department of Medical Genetics, College of Basic Medicine, Army Medical University
Accession: SCV003935199.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Age: 30-39 years
Sex: female
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Pathogenic
(Sep 01, 2001)
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no assertion criteria provided
Method: literature only
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ECTODERMAL DYSPLASIA AND IMMUNODEFICIENCY 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032443.9
First in ClinVar: Apr 04, 2013 Last updated: Dec 17, 2023 |
Comment on evidence:
In 2 brothers (family 4) with lethal hypohidrotic ectodermal dysplasia with immune deficiency-1 (EDAID1; 300291), Zonana et al. (2000) identified a hemizygous 1-bp duplication (c.1167_1168dupC) … (more)
In 2 brothers (family 4) with lethal hypohidrotic ectodermal dysplasia with immune deficiency-1 (EDAID1; 300291), Zonana et al. (2000) identified a hemizygous 1-bp duplication (c.1167_1168dupC) in exon 10 of the IKBKG gene, predicted to result in a frameshift, the addition of novel amino acids at codons 390-393, and premature termination at codon 394. The duplication resulted from an insertion of a cytosine within a wildtype run of 7 cytosines in exon 10. The mutation was predicted to delete the putative zinc finger domain. The patients also had osteopetrosis and died of mycobacterial infection. Kosaki et al. (2001) described an unusual family in which a girl with this heterozygous mutation had skin abnormalities with streaky hyperpigmented macules, features of ectodermal dysplasia, including decreased sweating, thin hair, and hypodontia, and onset of recurrent infections around 4 years of age. She later developed pulmonary and renovascular hypertension, and died at age 11 years after cardiac catheterization. IgD and IgE were increased. X-inactivation studies of peripheral blood leukocytes showed a random pattern. The mother had hyperpigmented macules in a streaky configuration on the trunk and limbs at several weeks of age, but never developed immunodeficiency; DNA from the mother was not studied. The family had previously been reported by Akiyama et al. (1994) as having 'linear and whorled nevoid hypermelanosis (see 614323). Zonana and Ferguson (2001) noted that the findings of random X inactivation in the girl reported by Kosaki et al. (2001) was unusual, and postulated that other molecular mechanisms may have been at play, including the possibility of skewed X inactivation in different leukocyte subsets. These authors emphasized that this phenotype in females is a very rare occurrence, and that generally, only males are affected. Aradhya et al. (2001) identified the same frameshift mutation, referred to as a 1-bp duplication in the 7-cytosine tract (1161_1162dupC) of the IKBKG gene, in a male patient (family XL344) with EDAID1. Female members of the family, who were heterozygous for the mutation, had typical signs of incontinentia pigmenti (IP; 308300). The affected male exhibited skin pigmentation, dental problems, and immune dysfunction. He suffered multiple episodes of infection, including meningitis and pneumonia, due to poor lymphocyte function and remarkably low levels of circulating IgG. He also exhibited heat intolerance with hyperthermia, anhidrosis, eczema, and fine sparse hair, which led to a diagnosis of ectodermal dysplasia. At the age of 3 years he was receiving routine supplements of IgG to prevent recurrent infections. He showed hepatosplenomegaly and had contracted Mycobacterium avium intracellulare, an infection common among patients with AIDS. Aradhya et al. (2001) identified a different mutation involving the same C(7) tract in another family; see 300248.0012. (less)
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Pathogenic
(Sep 01, 2001)
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no assertion criteria provided
Method: literature only
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INCONTINENTIA PIGMENTI
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001335503.3
First in ClinVar: Jun 13, 2020 Last updated: Dec 17, 2023 |
Comment on evidence:
In 2 brothers (family 4) with lethal hypohidrotic ectodermal dysplasia with immune deficiency-1 (EDAID1; 300291), Zonana et al. (2000) identified a hemizygous 1-bp duplication (c.1167_1168dupC) … (more)
In 2 brothers (family 4) with lethal hypohidrotic ectodermal dysplasia with immune deficiency-1 (EDAID1; 300291), Zonana et al. (2000) identified a hemizygous 1-bp duplication (c.1167_1168dupC) in exon 10 of the IKBKG gene, predicted to result in a frameshift, the addition of novel amino acids at codons 390-393, and premature termination at codon 394. The duplication resulted from an insertion of a cytosine within a wildtype run of 7 cytosines in exon 10. The mutation was predicted to delete the putative zinc finger domain. The patients also had osteopetrosis and died of mycobacterial infection. Kosaki et al. (2001) described an unusual family in which a girl with this heterozygous mutation had skin abnormalities with streaky hyperpigmented macules, features of ectodermal dysplasia, including decreased sweating, thin hair, and hypodontia, and onset of recurrent infections around 4 years of age. She later developed pulmonary and renovascular hypertension, and died at age 11 years after cardiac catheterization. IgD and IgE were increased. X-inactivation studies of peripheral blood leukocytes showed a random pattern. The mother had hyperpigmented macules in a streaky configuration on the trunk and limbs at several weeks of age, but never developed immunodeficiency; DNA from the mother was not studied. The family had previously been reported by Akiyama et al. (1994) as having 'linear and whorled nevoid hypermelanosis (see 614323). Zonana and Ferguson (2001) noted that the findings of random X inactivation in the girl reported by Kosaki et al. (2001) was unusual, and postulated that other molecular mechanisms may have been at play, including the possibility of skewed X inactivation in different leukocyte subsets. These authors emphasized that this phenotype in females is a very rare occurrence, and that generally, only males are affected. Aradhya et al. (2001) identified the same frameshift mutation, referred to as a 1-bp duplication in the 7-cytosine tract (1161_1162dupC) of the IKBKG gene, in a male patient (family XL344) with EDAID1. Female members of the family, who were heterozygous for the mutation, had typical signs of incontinentia pigmenti (IP; 308300). The affected male exhibited skin pigmentation, dental problems, and immune dysfunction. He suffered multiple episodes of infection, including meningitis and pneumonia, due to poor lymphocyte function and remarkably low levels of circulating IgG. He also exhibited heat intolerance with hyperthermia, anhidrosis, eczema, and fine sparse hair, which led to a diagnosis of ectodermal dysplasia. At the age of 3 years he was receiving routine supplements of IgG to prevent recurrent infections. He showed hepatosplenomegaly and had contracted Mycobacterium avium intracellulare, an infection common among patients with AIDS. Aradhya et al. (2001) identified a different mutation involving the same C(7) tract in another family; see 300248.0012. (less)
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Pathogenic
(May 10, 2023)
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no assertion criteria provided
Method: clinical testing
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Immunodeficiency 33
Affected status: yes
Allele origin:
maternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV004812036.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
Clinical Features:
Conical tooth (present) , Frontal bossing (present) , Immunodeficiency (present)
Age: 0-9 years
Sex: male
Tissue: Blood
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not provided
(-)
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no classification provided
Method: literature only
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Incontinentia pigmenti syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002553187.2
First in ClinVar: Jul 28, 2022 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Incontinentia Pigmenti. | Adam MP | - | 2017 | PMID: 20301645 |
A male infant with anhidrotic ectodermal dysplasia/immunodeficiency accompanied by incontinentia pigmenti and a mutation in the NEMO pathway. | Chang TT | Journal of the American Academy of Dermatology | 2008 | PMID: 18222329 |
Female patient showing hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). | Kosaki K | American journal of human genetics | 2001 | PMID: 11484156 |
Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-gamma). | Aradhya S | American journal of human genetics | 2001 | PMID: 11179023 |
A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). | Zonana J | American journal of human genetics | 2000 | PMID: 11047757 |
Familial linear and whorled nevoid hypermelanosis. | Akiyama M | Journal of the American Academy of Dermatology | 1994 | PMID: 8169255 |
Text-mined citations for rs782178147 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.