Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_001134831.2(AHI1):c.2105C>A(p.Thr702Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T702M) has been classified as Likely pathogenic.
AHI1 (HGNC:21575): (Abelson helper integration site 1) This gene is apparently required for both cerebellar and cortical development in humans. This gene mutations cause specific forms of Joubert syndrome-related disorders. Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a repeat WD 3 (size 40) in uniprot entity AHI1_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_001134831.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-135433188-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 568060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Loss of phosphorylation at T702 (P = 0.1031);Loss of phosphorylation at T702 (P = 0.1031);Loss of phosphorylation at T702 (P = 0.1031);Loss of phosphorylation at T702 (P = 0.1031);