rs863225220
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024809.5(TCTN2):c.1626del(p.Asp543IlefsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,610,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
TCTN2
NM_024809.5 frameshift
NM_024809.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.416
Genes affected
TCTN2 (HGNC:25774): (tectonic family member 2) This gene encodes a type I membrane protein that belongs to the tectonic family. Studies in mice suggest that this protein may be involved in hedgehog signaling, and essential for ciliogenesis. Mutations in this gene are associated with Meckel syndrome type 8. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-123704544-CT-C is Pathogenic according to our data. Variant chr12-123704544-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 217697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123704544-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TCTN2 | NM_024809.5 | c.1626del | p.Asp543IlefsTer11 | frameshift_variant | 15/18 | ENST00000303372.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCTN2 | ENST00000303372.7 | c.1626del | p.Asp543IlefsTer11 | frameshift_variant | 15/18 | 1 | NM_024809.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000133 AC: 2AN: 150324Hom.: 0 Cov.: 30
GnomAD3 genomes
?
AF:
AC:
2
AN:
150324
Hom.:
Cov.:
30
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249106Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134684
GnomAD3 exomes
AF:
AC:
1
AN:
249106
Hom.:
AF XY:
AC XY:
1
AN XY:
134684
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1460472Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726436
GnomAD4 exome
AF:
AC:
20
AN:
1460472
Hom.:
Cov.:
31
AF XY:
AC XY:
8
AN XY:
726436
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000133 AC: 2AN: 150324Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1AN XY: 73324
GnomAD4 genome
?
AF:
AC:
2
AN:
150324
Hom.:
Cov.:
30
AF XY:
AC XY:
1
AN XY:
73324
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 16, 2022 | For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Asp543Ilefs*11) in the TCTN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCTN2 are known to be pathogenic (PMID: 21565611). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 26092869). ClinVar contains an entry for this variant (Variation ID: 217697). - |
Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at