rs786204788

Variant names:

• chr12-123706833-T-A
• rs786204788
• NM_024809.5:c.1877T>A

Your query was ambiguous. Multiple possible variants found:

• chr12-123706833-T-A
• chr12-123706833-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024809.5(TCTN2):​c.1877T>A​(p.Leu626*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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: Genomes: not found (cov: 32)
• Consequence: TCTN2 NM_024809.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.354

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 12-123706833-T-A is Pathogenic according to our data. Variant chr12-123706833-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 189247.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.1877T>A	p.Leu626*	stop_gained	Exon 16 of 18	ENST00000303372.7	NP_079085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.1877T>A	p.Leu626*	stop_gained	Exon 16 of 18	1	NM_024809.5	ENSP00000304941.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial aplasia of the vermis Pathogenic:1

Jan 20, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Leu626X variant in TCTN2 has not been previously identified in individuals with Joubert syndrome or in large population studies. However, this nonsense variant leads to a premature termination codon at position 626, which is predicted to lead to a truncated or absent protein. Loss-of-function variants in the TCTN2 gene, including another nonsense variant in this exon, have been previously reported in individuals with autosomal recessive ciliopathies including Joubert syndrome (Sang 2011) and Meckel-Gruber syndrome (Shaheen 2011). In summary, this variant meets our criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Benign	0.97
Eigen	Benign	0.17
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.059	N
Vest4		0.27
GERP RS		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786204788; hg19: chr12-124191380;