16-89284129-CTTTTT-CT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_013275.6(ANKRD11):c.2409_2412del(p.Glu805ArgfsTer57) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
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-CTTTT-C is Pathogenic according to our data. Variant chr16-89284129-CTTTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 426843.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.2409_2412del | p.Glu805ArgfsTer57 | frameshift_variant | 9/13 | ENST00000301030.10 | |
ANKRD11 | NM_001256182.2 | c.2409_2412del | p.Glu805ArgfsTer57 | frameshift_variant | 10/14 | ||
ANKRD11 | NM_001256183.2 | c.2409_2412del | p.Glu805ArgfsTer57 | frameshift_variant | 9/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANKRD11 | ENST00000301030.10 | c.2409_2412del | p.Glu805ArgfsTer57 | frameshift_variant | 9/13 | 5 | NM_013275.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
KBG syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 02, 2016 | The p.Glu805Argfs*57 variant in ANKRD11 has not been reported in patients and is absent from large population studies, though the ability of these studies to ac curately detect indels may be limited. This variant is predicted to cause a fram eshift, which alters the protein?s amino acid sequence beginning at position 805 and leads to a premature termination codon 57 amino acids downstream. This alte ration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the ANKRD11 gene is an established disease mecha nism in KBG syndrome. In summary, the p.Glu805Argfs*57 variant in ANKRD11 meets criteria to be classified as likely pathogenic for KBG syndrome in an autosomal dominant manner based on predicted impact to the protein. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Medicine, Institute for Basic Research in Developmental Disabilities | - | KBG syndrome - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 13, 2023 | 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30609409, 35970914) - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at