chr16-89282770-CTT-C
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
Consequence
NM_013275.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
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 Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
KBG syndrome Pathogenic:5
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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. -
KBG syndrome -
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. -
ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM6 moderated -
not provided Pathogenic:3
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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) -
ANKRD11: PVS1, PM2, PM6, PS4:Moderate -
Inborn genetic diseases Pathogenic:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at