rs374349989

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_024809.5(TCTN2):c.1506-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000205 in 1,608,974 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TCTN2
NM_024809.5 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.98

Publications

8 publications found

Variant links:

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]

TCTN2 Gene-Disease associations (from GenCC):

Joubert syndrome 24
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TCTN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.051098377 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4, offset of -48, new splice context is: ttcactggaaatgactttAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-123699702-A-G is Pathogenic according to our data. Variant chr12-123699702-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN2	NM_024809.5 link	c.1506-2A>G		splice_acceptor_variant, intron_variant	Intron 13 of 17	ENST00000303372.7	NP_079085.2	Q96GX1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7 link	c.1506-2A>G		splice_acceptor_variant, intron_variant	Intron 13 of 17	1	NM_024809.5	ENSP00000304941.5		Q96GX1-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251140

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1456864

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

725018

show subpopulations

African (AFR)

AF:

0.0000900

AC:

AN:

33316

American (AMR)

AF:

0.0000224

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39446

South Asian (SAS)

AF:

0.000116

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1108070

Other (OTH)

AF:

0.0000499

AC:

AN:

60150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000483

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.038550), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jul 14, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TCTN2: PVS1, PM2 -

Feb 25, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that normal splicing is abolished and two abberant transcripts are created (Shaheen et al., 2011); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21462283, 26729329, 23169490, 31428121, 32055034, 31589614, 32552793) -

Joubert syndrome 24

Pathogenic:1

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

- -

Meckel syndrome, type 8

Pathogenic:1

Jun 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Joubert syndrome and related disorders

Pathogenic:1

Feb 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TCTN2 c.1506-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence confirming that this variant affects mRNA splicing (Maddirevula_2020). The variant allele was found at a frequency of 1.6e-05 in 251140 control chromosomes (gnomAD). c.1506-2A>G has been reported in the literature in multiple individuals affected with Joubert Syndrome And Related Disorders (e.g. Shaheen_2016, Maddirevula_2020, Watson_2016). These data indicate that the variant is very likely to be associated with disease. ClinVar contains an entry for this variant (Variation ID: 31076). Based on the evidence outlined above, the variant was classified as pathogenic. -

TCTN2-related disorder

Pathogenic:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TCTN2 c.1506-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1506-2A>G variant has been reported in three studies in which it is found in a homozygous state in at least six patients and in a heterozygous state in one patient in whom a second variant was not identified (Shaheen et al. 2011; Shaheen et al. 2013; Watson et al. 2016). Three of the homozygotes were diagnosed with Meckel syndrome and three patients were noted to be on the Joubert-Meckel syndrome spectrum but the individual clinical phenotypes were not provided (Watson et al. 2016). The c.1506-2A>G variant was absent from at least 192 controls and is reported at a frequency of 0.00012 in the European-American population of the Exome Sequencing Project but this is based on one allele only. RT-PCR experiments showed the variant completely abolished normal splicing and created two aberrant transcripts (Shaheen et al. 2011). Based on the evidence, the c.1506-2A>G variant is classified as pathogenic for TCTN2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Pathogenic:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 13 of the TCTN2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TCTN2 are known to be pathogenic (PMID: 21565611). This variant is present in population databases (rs374349989, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with clinical features of TCTN2-related conditions (PMID: 21462283, 31428121). ClinVar contains an entry for this variant (Variation ID: 31076). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Meckel syndrome, type 8;C4084841:Joubert syndrome 24

Pathogenic:1

Jan 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meckel syndrome, type 6

Pathogenic:1

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

PhyloP100

6.0

GERP RS

5.9

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AL_spliceai

1.0

Position offset: 2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over