rs869312841
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006734.4(HIVEP2):c.2827C>T(p.Arg943*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006734.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 35
GnomAD4 genome
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 43 Pathogenic:9
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Variant summary: HIVEP2 c.2827C>T (p.Arg943X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 249538 control chromosomes (gnomAD). c.2827C>T has been reported in the literature in at least one individual affected with Intellectual Disability, Autosomal Dominant 43, where it was found to be de novo (e.g. Quental_2022). These data suggest the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 36588750). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-10-13 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -
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PVS1+PM2_Supporting+PS4_Supporting+PS2_Moderate -
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Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000224791, PMID:26153216). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Variant confirmed as disease-causing by referring clinical team -
not provided Pathogenic:4
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For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 224791). This premature translational stop signal has been observed in individual(s) with intellectual disability (PMID: 26153216). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg943*) in the HIVEP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HIVEP2 are known to be pathogenic (PMID: 27003583). -
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26153216) -
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Intellectual disability Pathogenic:1
PVS1,PS2_VeryStrong,PM2,PP4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at