16-88709982-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3PP5BP4
The NM_001012759.3(CTU2):c.188T>C(p.Leu63Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00105 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L63V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001012759.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTU2 | NM_001012759.3 | c.188T>C | p.Leu63Pro | missense_variant | 3/15 | ENST00000453996.7 | |
CTU2 | NM_001318507.2 | c.188T>C | p.Leu63Pro | missense_variant | 3/15 | ||
CTU2 | NM_001012762.3 | c.188T>C | p.Leu63Pro | missense_variant | 3/14 | ||
CTU2 | NM_001318513.2 | c.-39-241T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTU2 | ENST00000453996.7 | c.188T>C | p.Leu63Pro | missense_variant | 3/15 | 1 | NM_001012759.3 | P2 | |
ENST00000616106.1 | n.456A>G | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes AF: 0.000565 AC: 86AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000796 AC: 200AN: 251340Hom.: 0 AF XY: 0.000795 AC XY: 108AN XY: 135888
GnomAD4 exome AF: 0.00110 AC: 1610AN: 1461634Hom.: 0 Cov.: 32 AF XY: 0.00104 AC XY: 755AN XY: 727104
GnomAD4 genome AF: 0.000565 AC: 86AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36AN XY: 74492
ClinVar
Submissions by phenotype
Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | - | - - |
CTU2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2023 | The CTU2 c.188T>C variant is predicted to result in the amino acid substitution p.Leu63Pro. This variant in the compound heterozygous condition along with a second variant in this gene was reported in one individual with Intellectual disability (Table 4, Helsmoortel et al. 2015. PubMed ID: 25081361) and was reported in the homozygous condition in two unrelated individuals with DREAM‐PL syndrome (dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly) (Table 1, Shaheen et al. 2019. PubMed ID: 31301155). This variant is reported in 0.15% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change replaces leucine with proline at codon 63 of the CTU2 protein (p.Leu63Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs147948789, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of DREAM-PL (dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly,polydactyly, and lissencephaly) (PMID: 25081361, 31301155). ClinVar contains an entry for this variant (Variation ID: 635410). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTU2 protein function with a positive predictive value of 80%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at