Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_015158.5(KANK1):āc.149A>Gā(p.Asp50Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D50V) has been classified as Likely benign.
KANK1 (HGNC:19309): (KN motif and ankyrin repeat domains 1) The protein encoded by this gene belongs to the Kank family of proteins, which contain multiple ankyrin repeat domains. This family member functions in cytoskeleton formation by regulating actin polymerization. This gene is a candidate tumor suppressor for renal cell carcinoma. Mutations in this gene cause cerebral palsy spastic quadriplegic type 2, a central nervous system development disorder. A t(5;9) translocation results in fusion of the platelet-derived growth factor receptor beta gene (PDGFRB) on chromosome 5 with this gene in a myeloproliferative neoplasm featuring severe thrombocythemia. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 20. [provided by RefSeq, Dec 2014]
Uncertain significance, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Nov 11, 2024
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 50 of the KANK1 protein (p.Asp50Gly). This variant is present in population databases (rs61737971, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with KANK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1986118). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -