rs886039902
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_013275.6(ANKRD11):c.2408_2412del(p.Lys803ArgfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000206 in 1,456,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
ANKRD11
NM_013275.6 frameshift
NM_013275.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.98
Genes affected
ANKRD11 (HGNC:21316): (ankyrin repeat domain containing 11) This locus encodes an ankryin repeat domain-containing protein. The encoded protein inhibits ligand-dependent activation of transcription. Mutations in this gene have been associated with KBG syndrome, which is characterized by macrodontia, distinctive craniofacial features, short stature, skeletal anomalies, global developmental delay, seizures and intellectual disability. Alternatively spliced transcript variants have been described. Related pseudogenes exist on chromosomes 2 and X. [provided by RefSeq, Jan 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-89284129-CTTTTT-C is Pathogenic according to our data. Variant chr16-89284129-CTTTTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 266033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANKRD11 | NM_013275.6 | c.2408_2412del | p.Lys803ArgfsTer5 | frameshift_variant | 9/13 | ENST00000301030.10 | |
ANKRD11 | NM_001256182.2 | c.2408_2412del | p.Lys803ArgfsTer5 | frameshift_variant | 10/14 | ||
ANKRD11 | NM_001256183.2 | c.2408_2412del | p.Lys803ArgfsTer5 | frameshift_variant | 9/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANKRD11 | ENST00000301030.10 | c.2408_2412del | p.Lys803ArgfsTer5 | frameshift_variant | 9/13 | 5 | NM_013275.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1456390Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 723966
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
KBG syndrome Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | May 09, 2018 | - - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Sep 15, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 06, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 23, 2022 | This premature translational stop signal has been observed in individuals with KBG syndrome (PMID: 27667800). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 266033). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys803Argfs*5) in the ANKRD11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANKRD11 are known to be pathogenic (PMID: 21782149, 25125236, 25413698, 25652421). - |
Pathogenic, criteria provided, single submitter | research | Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano | Nov 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 09, 2020 | - - |
Pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Sep 10, 2018 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-10 and interpreted as Pathogenic. Variant was initially reported on 2018-01-09 by GTR ID of laboratory name 506154. The reporting laboratory might also submit to ClinVar. - |
Pathogenic, no assertion criteria provided | clinical testing | Autoinflammatory diseases unit, CHU de Montpellier | Apr 15, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | May 28, 2020 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | ANKRD11: PVS1, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Dec 12, 2022 | PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2021 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27667800, 25533962, 28191890, 29224748, 28135719, 32124548) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Global developmental delay Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Institute for Human Genetics, University Hospital Essen | Jan 22, 2021 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2022 | The c.2408_2412delAAAAA (p.K803Rfs*5) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 5 nucleotides from position 2408 to 2412, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as de novo in multiple unrelated individuals with clinical features of KBG syndrome (Parenti, 2021; Gnazzo, 2020). Additional heterozygous individuals with ANKRD11 variants have been reported in the literature (Low, 2016; Bestetti, 2022). Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at