chr12-123694870-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024809.5(TCTN2):c.1128T>C(p.Pro376Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,611,480 control chromosomes in the GnomAD database, including 177,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 24168 hom., cov: 32)

Exomes 𝑓: 0.45 ( 153799 hom. )

Consequence

TCTN2
NM_024809.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.320

Publications

29 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 12-123694870-T-C is Benign according to our data. Variant chr12-123694870-T-C is described in ClinVar as Benign. ClinVar VariationId is 126283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.32 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN2	NM_024809.5 link	c.1128T>C	p.Pro376Pro	synonymous_variant	Exon 10 of 18	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.1128T>C	p.Pro376Pro	synonymous_variant	Exon 10 of 18	1	NM_024809.5	ENSP00000304941.5		Q96GX1-1

Frequencies

GnomAD3 genomes

AF:

0.530

AC:

80470

AN:

151964

Hom.:

24113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.822

Gnomad AMI

AF:

0.552

Gnomad AMR

AF:

0.399

Gnomad ASJ

AF:

0.405

Gnomad EAS

AF:

0.150

Gnomad SAS

AF:

0.464

Gnomad FIN

AF:

0.347

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.450

Gnomad OTH

AF:

0.492

GnomAD2 exomes

AF:

0.424

AC:

106367

AN:

251142

AF XY:

0.427

show subpopulations

Gnomad AFR exome

AF:

0.834

Gnomad AMR exome

AF:

0.277

Gnomad ASJ exome

AF:

0.400

Gnomad EAS exome

AF:

0.153

Gnomad FIN exome

AF:

0.360

Gnomad NFE exome

AF:

0.450

Gnomad OTH exome

AF:

0.430

GnomAD4 exome

AF:

0.449

AC:

655228

AN:

1459398

Hom.:

153799

Cov.:

AF XY:

0.450

AC XY:

326406

AN XY:

725976

show subpopulations

African (AFR)

AF:

0.841

AC:

28119

AN:

33426

American (AMR)

AF:

0.292

AC:

13029

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

10315

AN:

26068

East Asian (EAS)

AF:

0.121

AC:

4806

AN:

39656

South Asian (SAS)

AF:

0.492

AC:

42388

AN:

86218

European-Finnish (FIN)

AF:

0.356

AC:

18971

AN:

53306

Middle Eastern (MID)

AF:

0.469

AC:

2702

AN:

5756

European-Non Finnish (NFE)

AF:

0.457

AC:

507534

AN:

1110020

Other (OTH)

AF:

0.454

AC:

27364

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

16949

33898

50848

67797

84746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15164

30328

45492

60656

75820

<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:

0.530

AC:

80579

AN:

152082

Hom.:

24168

Cov.:

AF XY:

0.521

AC XY:

38724

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.822

AC:

34127

AN:

41514

American (AMR)

AF:

0.399

AC:

6093

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.405

AC:

1406

AN:

3470

East Asian (EAS)

AF:

0.149

AC:

774

AN:

5184

South Asian (SAS)

AF:

0.463

AC:

2232

AN:

4822

European-Finnish (FIN)

AF:

0.347

AC:

3658

AN:

10546

Middle Eastern (MID)

AF:

0.517

AC:

152

AN:

294

European-Non Finnish (NFE)

AF:

0.450

AC:

30593

AN:

67966

Other (OTH)

AF:

0.495

AC:

1045

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1687

3373

5060

6746

8433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.472

Hom.:

35393

Bravo

AF:

0.541

Asia WGS

AF:

0.357

AC:

1245

AN:

3478

EpiCase

AF:

0.453

EpiControl

AF:

0.453

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meckel syndrome, type 8

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:3

Jan 08, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Joubert syndrome 24

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

5.6

(source)

DANN

Benign

0.55

PhyloP100

0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over