11-61397797-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001173990.3(TMEM216):c.253C>T(p.Arg85Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R85R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001173990.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM216 | NM_001173990.3 | c.253C>T | p.Arg85Ter | stop_gained | 4/5 | ENST00000515837.7 | |
TMEM216 | NM_001173991.3 | c.253C>T | p.Arg85Ter | stop_gained | 4/5 | ||
TMEM216 | NM_016499.6 | c.70C>T | p.Arg24Ter | stop_gained | 4/5 | ||
TMEM216 | NM_001330285.2 | c.70C>T | p.Arg24Ter | stop_gained | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM216 | ENST00000515837.7 | c.253C>T | p.Arg85Ter | stop_gained | 4/5 | 2 | NM_001173990.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152206Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000804 AC: 20AN: 248910Hom.: 0 AF XY: 0.0000593 AC XY: 8AN XY: 134992
GnomAD4 exome AF: 0.000153 AC: 223AN: 1461166Hom.: 0 Cov.: 29 AF XY: 0.000140 AC XY: 102AN XY: 726880
GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152206Hom.: 0 Cov.: 31 AF XY: 0.0000941 AC XY: 7AN XY: 74352
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 24, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 27, 2023 | Observed in homozygous state in two siblings with Meckel syndrome in published literature (Valente et al., 2010; Szymanska et al., 2012) and in a fetus with encephalocele, kidney anomaly, eye abnormality, microcephaly, club foot, and short limbs previously tested at GeneDx, and not observed in homozygous state in controls; Observed in the heterozygous state with another variant in the TMEM216 gene in a patient with Joubert syndrome in published literature; however, it is unknown whether the two variants were present in cis or trans (Bachmann-Gagescu et al., 2015; Summers et al., 2017); 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; This variant is associated with the following publications: (PMID: 20512146, 21068128, 23351400, 26092869, 28497568, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 13, 2023 | PM2, PS3, PVS1 - |
Joubert syndrome 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 05, 2018 | Variant summary: TMEM216 c.253C>T (p.Arg85X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.7e-05 in 276782 control chromosomes. This frequency is not higher than expected for a pathogenic variant in TMEM216 causing Joubert Syndrome 2 (8.7e-05 vs 0.0039), allowing no conclusion about variant significance. c.253C>T has been reported in the literature in individuals affected with Meckel syndrome 2 or Joubert Syndrome 2 (Valente 2010, Summers 2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating the loss of protein expression and a failure in ciliogenesis and centrosome docking (Valente 2010). The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 31, 2023 | - - |
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Joubert syndrome 2;C1864148:Meckel syndrome, type 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 22, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 02, 2014 | - - |
TMEM216-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 11, 2018 | The TMEM216 c.253C>T (p.Arg85Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg85Ter variant has been reported in at least two studies in which it is found in at least three individuals, including two siblings with Meckel syndrome who carried the variant in a homozygous state and one individual with Joubert syndrome who carried the variant in a compound heterozygous state (Valente et al. 2010; Bachmann-Gogescu et al. 2015). The p.Arg85Ter variant was absent from 500 controls, but is reported at a frequency of 0.00003 in the total population from the Exome Aggregation Consortium. In fibroblasts that were homozygous for the p.Arg85Ter variant, there was failure of ciliogenesis after 48h compared to controls (Valente et al. 2010). Further, this variant protein was not observed at the base of cilia in kidney cells, whereas wild type protein was observed at this location. Based on the evidence and the potential impact of stop-gained variants, the p.Arg85Ter variant is classified as pathogenic for TMEM216-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 27, 2023 | The TMEM216 c.253C>T variant is predicted to result in premature protein termination (p.Arg85*). This variant has been reported in the homozygous state in two fetuses with Meckel-Gruber syndrome from one family (Valente et al 2010. PubMed ID: 20512146). This variant has also been reported in the homozygous or heterozygous states in individuals with Joubert syndrome (Bachmann-Gagescu et al. 2015. PubMed ID: 26092869. Table S5; Summers et al. 2017. PubMed ID: 28497568. Table S2; Szymanska et al. 2012. PubMed ID: 23351400). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-61165269-C-T). Nonsense variants in TMEM216 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Meckel syndrome, type 2 Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change creates a premature translational stop signal (p.Arg85*) in the TMEM216 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM216 are known to be pathogenic (PMID: 20512146). This variant is present in population databases (rs11230683, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Meckel syndrome or Joubert syndrome (PMID: 20512146, 23351400, 26092869, 28497568). ClinVar contains an entry for this variant (Variation ID: 56384). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at