chr16-89282770-CTT-C
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_013275.6(ANKRD11):c.3770_3771delAA(p.Lys1257ArgfsTer25) 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 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: 2.76
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 16-89282770-CTT-C is Pathogenic according to our data. Variant chr16-89282770-CTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89282770-CTT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ANKRD11 | NM_013275.6 | c.3770_3771delAA | p.Lys1257ArgfsTer25 | frameshift_variant | Exon 9 of 13 | ENST00000301030.10 | NP_037407.4 | |
| ANKRD11 | NM_001256182.2 | c.3770_3771delAA | p.Lys1257ArgfsTer25 | frameshift_variant | Exon 10 of 14 | NP_001243111.1 | ||
| ANKRD11 | NM_001256183.2 | c.3770_3771delAA | p.Lys1257ArgfsTer25 | frameshift_variant | Exon 9 of 13 | NP_001243112.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
KBG syndrome Pathogenic:5
| Pathogenic, no assertion criteria provided | clinical testing | Autoinflammatory diseases unit, CHU de Montpellier | Jun 24, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This frameshift mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory as a de novo finding in a 4-year-old female with delays, hypotonia, anxiety, short stuture, atrial septal defect. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Medicine, Institute for Basic Research in Developmental Disabilities | - | KBG syndrome - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | May 15, 2020 | The de novo c.3770_3771del (p.Lys1257ArgfsTer25) variant identified in the ANKRD11 gene is the deletion of two nucleotides, resulting in the frameshift of the amino acid 1257/2664 (coding exon 9/13), and is predicted to lead to the premature termination of the protein approximately 25 amino acids downstream of the frameshift. This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. This variant is reported in ClinVar as Pathogenic (VarID: 265324) by two independent clinical labs who state the variant was identified de novo in affected individuals. The c.3770_3771del (p.Lys1257ArgfsTer25) variant has also been reported in the literature in a male with feeding difficulties, short stature, hyperopic astigmatism, hearing loss, and Autism Spectrum Disorder [PMID:28529015], and a female with KBG syndrome [PMID:31703437]. Given its presence de novo in this individual, its deleterious nature, absence in population databases, and observation in multiple affected individuals in the literature, the c.3770_3771del (p.Lys1257ArgfsTer25) variant identified in the ANKRD11 gene is reported here as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jul 06, 2022 | ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM6 moderated - |
not provided Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jan 19, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28529015, 31703437, 32124548, 25326635, 28135719) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2025 | ANKRD11: PVS1, PM2, PM6, PS4:Moderate - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2022 | The c.3770_3771delAA (p.K1257Rfs*25) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 2 nucleotides from position 3770 to 3771, causing a translational frameshift with a predicted alternate stop codon after 25 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 a de novo event in multiple unrelated individuals with KBG syndrome (Meyer, 2017; Gnazzo, 2020). Based on the available evidence, this alteration is classified as pathogenic. - |
Rare genetic intellectual disability Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Computational scores
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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