12-123671310-TG-TGG

Variant names:

• chr12-123671310-T-TG
• rs863225222
• NM_024809.5:c.76dupG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_024809.5(TCTN2):​c.76dupG​(p.Asp26GlyfsTer52) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCTN2 NM_024809.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.591

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-123671310-T-TG is Pathogenic according to our data. Variant chr12-123671310-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 217700.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.76dupG	p.Asp26GlyfsTer52	frameshift_variant	Exon 1 of 18	ENST00000303372.7	NP_079085.2
TCTN2	NM_001143850.3	c.76dupG	p.Asp26GlyfsTer52	frameshift_variant	Exon 1 of 18		NP_001137322.1
TCTN2	NM_001410989.1	c.76dupG	p.Asp26GlyfsTer52	frameshift_variant	Exon 1 of 17		NP_001397918.1
TCTN2	XM_017019974.2	c.76dupG	p.Asp26GlyfsTer52	frameshift_variant	Exon 1 of 17		XP_016875463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.76dupG	p.Asp26GlyfsTer52	frameshift_variant	Exon 1 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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 24 Pathogenic:1

May 13, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial aplasia of the vermis Pathogenic:1

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863225222; hg19: chr12-124155857;