rs878855327
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_013275.6(ANKRD11):c.6792del(p.Ala2265ProfsTer72) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P2264P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ANKRD11
NM_013275.6 frameshift
NM_013275.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -3.15
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 16-89279749-CG-C is Pathogenic according to our data. Variant chr16-89279749-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 242348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89279749-CG-C is described in Lovd as [Pathogenic]. Variant chr16-89279749-CG-C is described in Lovd as [Likely_pathogenic]. Variant chr16-89279749-CG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANKRD11 | NM_013275.6 | c.6792del | p.Ala2265ProfsTer72 | frameshift_variant | 9/13 | ENST00000301030.10 | |
ANKRD11 | NM_001256182.2 | c.6792del | p.Ala2265ProfsTer72 | frameshift_variant | 10/14 | ||
ANKRD11 | NM_001256183.2 | c.6792del | p.Ala2265ProfsTer72 | frameshift_variant | 9/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANKRD11 | ENST00000301030.10 | c.6792del | p.Ala2265ProfsTer72 | frameshift_variant | 9/13 | 5 | NM_013275.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1371814Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 675452
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1371814
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33
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0
AN XY:
675452
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
KBG syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 26, 2021 | The de novo heterozygous c.6792delC (p.Ala2265ProfsTer72) frameshift variant located in exon 9 (of 13) of the ANKRD11 gene alters the wild type translational reading frame and is predicted to result in an absent or truncated protein product. A frameshift variant affecting the same codon and with identical predicted affect on the protein [c.6793delC (p.Ala2265Profs)] has been reported in a patient affected with moderate intellectual disability, seizures, hearing impairment, facial dysmorphism, myalgia, and abnormal biochemical findings (decreased Complex I & V, Complex III near 5% reference; See “additional file2: Table S1” of PMID: 28554332). The variant is absent from gnomAD(v3) database suggesting it is not a common benign allele in the populations represented in that database. Based on the available evidence, the de novo heterozygous c.6792delC (p.Ala2265ProfsTer72) frameshift variant identified in the ANKRD11 gene is reported as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jun 09, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2022 | 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); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) - |
Computational scores
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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