12-110626360-A-G

Variant names:

• chr12-110626360-A-G
• rs730882221
• NM_001082538.3:c.342-2A>G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001082538.3(TCTN1):​c.342-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000704 in 1,419,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TCTN1 NM_001082538.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.36

Genes affected

TCTN1 (HGNC:26113): (tectonic family member 1) This gene encodes a member of a family of secreted and transmembrane proteins. The orthologous gene in mouse functions downstream of smoothened and rab23 to modulate hedgehog signal transduction. This protein is a component of the tectonic-like complex, which forms a barrier between the ciliary axoneme and the basal body. A mutation in this gene was found in a family with Joubert syndrome-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-110626360-A-G is Pathogenic according to our data. Variant chr12-110626360-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 183312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110626360-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN1	NM_001082538.3	c.342-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 14	ENST00000397659.9	NP_001076007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN1	ENST00000397659.9	c.342-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 14	1	NM_001082538.3	ENSP00000380779.4
TCTN1	ENST00000551590.5	c.342-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 14	1		ENSP00000448735.1
TCTN1	ENST00000397655.7	c.342-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 14	1		ENSP00000380775.3
TCTN1	ENST00000397656.8	n.342-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 15	2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.342-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 15	5		ENSP00000437196.1
TCTN1	ENST00000495659.6	n.*100-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 14	2		ENSP00000436673.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1419522 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 703006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.19e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 13 Pathogenic:4

May 06, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 05, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Global developmental delay;CN228298:Typical Joubert syndrome MRI findings Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Benign	0.97
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.92	D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 11
DS_AL_spliceai		0.99		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882221; hg19: chr12-111064165;