16-89279749-CG-CGG
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_013275.6(ANKRD11):c.6792_6793insC(p.Ala2265ArgfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,371,808 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: 7.3e-7 ( 0 hom. )
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-C-CG is Pathogenic according to our data. Variant chr16-89279749-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 521294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ANKRD11 | NM_013275.6 | c.6792_6793insC | p.Ala2265ArgfsTer8 | frameshift_variant | 9/13 | ENST00000301030.10 | NP_037407.4 | |
ANKRD11 | NM_001256182.2 | c.6792_6793insC | p.Ala2265ArgfsTer8 | frameshift_variant | 10/14 | NP_001243111.1 | ||
ANKRD11 | NM_001256183.2 | c.6792_6793insC | p.Ala2265ArgfsTer8 | frameshift_variant | 9/13 | NP_001243112.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ANKRD11 | ENST00000301030.10 | c.6792_6793insC | p.Ala2265ArgfsTer8 | frameshift_variant | 9/13 | 5 | NM_013275.6 | ENSP00000301030 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 7.29e-7 AC: 1AN: 1371808Hom.: 0 Cov.: 33 AF XY: 0.00000148 AC XY: 1AN XY: 675444
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
KBG syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 20, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000521294 / PMID: 27605097). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 06, 2023 | This sequence change creates a premature translational stop signal (p.Ala2265Argfs*8) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with KBG syndrome (PMID: 27605097). ClinVar contains an entry for this variant (Variation ID: 521294). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Mar 29, 2024 | The ANKRD11 c.6792dup (p.Ala2265ArgfsTer8) variant has been reported as occurring de novo in at least one individual affected with KBG syndrome (Goldenberg A et al., PMID: 27605097). This variant has been reported in the ClinVar database as a germline pathogenic variant by eight submitters. This variant causes a frameshift by duplicating a single nucleotide, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. Additionally, other variants that introduce premature termination codons in this region have been described in affected individuals and are considered pathogenic (Goldenberg A et al., PMID: 27605097). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 03, 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; This variant is associated with the following publications: (PMID: 27605097, 34012832) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 02, 2023 | The c.6792dupC (p.A2265Rfs*8) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a duplication of C at position 6792, causing a translational frameshift with a predicted alternate stop codon after 8 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the CC allele has an overall frequency of 0.002% (3/123718) total alleles studied. The highest observed frequency was 0.03% (2/6560) of Ashkenazi Jewish alleles. The ANKRD11 p.A2265Rfs*8 alteration has been reported as a de novo finding in two unrelated individuals with features of KBG syndrome (Goldenberg, 2016; Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic. - |
Rare genetic intellectual disability Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
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