6-142771912-G-A
Variant summary
Our verdict is Pathogenic. The variant received 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
Publications
- intellectual disability, autosomal dominant 43Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P
- autosomal dominant non-syndromic intellectual disabilityInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_006734.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HIVEP2 | NM_006734.4 | MANE Select | c.2827C>T | p.Arg943* | stop_gained | Exon 5 of 10 | NP_006725.3 | ||
| HIVEP2 | NM_001438449.1 | c.2827C>T | p.Arg943* | stop_gained | Exon 5 of 10 | NP_001425378.1 | |||
| HIVEP2 | NM_001438450.1 | c.2827C>T | p.Arg943* | stop_gained | Exon 6 of 11 | NP_001425379.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HIVEP2 | ENST00000367603.8 | TSL:1 MANE Select | c.2827C>T | p.Arg943* | stop_gained | Exon 5 of 10 | ENSP00000356575.2 | ||
| HIVEP2 | ENST00000012134.7 | TSL:5 | c.2827C>T | p.Arg943* | stop_gained | Exon 4 of 9 | ENSP00000012134.2 | ||
| HIVEP2 | ENST00000367604.6 | TSL:5 | c.2827C>T | p.Arg943* | stop_gained | Exon 5 of 10 | ENSP00000356576.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 35
GnomAD4 genome
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 43 Pathogenic:11
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.
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.
Variant confirmed as disease-causing by referring clinical team
Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: 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. Damaging effect on gene or gene product predicted by in silico programs is uncertain [3Cnet: 0.96 (damaging >=0.6, benign <0.15)]. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000224791 /PMID: 26153216 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
not provided Pathogenic:4
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)
Intellectual disability Pathogenic:1
PVS1,PS2_VeryStrong,PM2,PP4
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at