Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PVS1_ModeratePM2BP6_Moderate
The NM_001134831.2(AHI1):c.2961+6_2961+21delinsGACTTTTTTAAAGTTTTAAA variant causes a splice donor, splice donor 5th base, intron 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 benign (★).
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 Uncertain_significance. Variant got 2 ACMG points.
PVS1
?
PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.054580897 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.4, offset of 0 (no position change), new splice context is: acaGTaagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
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;
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-135411327-AACTGCATAAAATAAA-TTTAAAACTTTAAAAAAGTC is Benign according to our data. Variant chr6-135411327-AACTGCATAAAATAAA-TTTAAAACTTTAAAAAAGTC is described in ClinVar as [Likely_benign]. Clinvar id is 241184.Status of the report is criteria_provided_single_submitter, 1 stars.