Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong
The NM_001352186.2(ANKS1B):c.3745G>A(p.Val1249Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000428 in 1,613,494 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
ANKS1B (HGNC:24600): (ankyrin repeat and sterile alpha motif domain containing 1B) This gene encodes a multi-domain protein that is predominantly expressed in brain and testis. This protein interacts with amyloid beta protein precursor (AbetaPP) and may have a role in normal brain development, and in the pathogenesis of Alzheimer's disease. Expression of this gene has been shown to be elevated in patients with pre-B cell acute lymphocytic leukemia associated with t(1;19) translocation. Alternatively spliced transcript variants encoding different isoforms (some with different subcellular localization, PMID:15004329) have been described for this gene. [provided by RefSeq, Aug 2011]
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP2
?
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, ANKS1B
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.042991698).
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 13, 2023
The c.3670G>A (p.V1224M) alteration is located in exon 25 (coding exon 25) of the ANKS1B gene. This alteration results from a G to A substitution at nucleotide position 3670, causing the valine (V) at amino acid position 1224 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -