12-123692742-T-C

Variant names:

• chr12-123692742-T-C
• rs7137946
• NM_024809.5:c.1099+19T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024809.5(TCTN2):​c.1099+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,580,840 control chromosomes in the GnomAD database, including 165,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (20708 hom., cov: 32)
  • Exomes 𝑓: 0.44 (144738 hom.)
• Consequence: TCTN2 NM_024809.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.336
• Publications: 24 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-123692742-T-C is Benign according to our data. Variant chr12-123692742-T-C is described in ClinVar as Benign. ClinVar VariationId is 126282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.1099+19T>C		intron_variant	Intron 9 of 17	ENST00000303372.7	NP_079085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.1099+19T>C		intron_variant	Intron 9 of 17	1	NM_024809.5	ENSP00000304941.5

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75795 AN: 151990 Hom.: 20662 Cov.: 32

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.464

GnomAD2 exomes AF: 0.414 AC: 103835 AN: 250978 AF XY: 0.419

Gnomad AFR exome AF: 0.731

Gnomad AMR exome AF: 0.267

Gnomad ASJ exome AF: 0.392

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.448

Gnomad OTH exome AF: 0.420

GnomAD4 exome AF: 0.441 AC: 629875 AN: 1428732 Hom.: 144738 Cov.: 27 AF XY: 0.442 AC XY: 315382 AN XY: 712948

African (AFR) AF: 0.734 AC: 23957 AN: 32646

American (AMR) AF: 0.281 AC: 12534 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 10037 AN: 25946

East Asian (EAS) AF: 0.120 AC: 4759 AN: 39600

South Asian (SAS) AF: 0.490 AC: 41941 AN: 85568

European-Finnish (FIN) AF: 0.356 AC: 19005 AN: 53356

Middle Eastern (MID) AF: 0.444 AC: 2405 AN: 5420

European-Non Finnish (NFE) AF: 0.452 AC: 489156 AN: 1082272

Other (OTH) AF: 0.440 AC: 26081 AN: 59256

GnomAD4 genome AF: 0.499 AC: 75890 AN: 152108 Hom.: 20708 Cov.: 32 AF XY: 0.491 AC XY: 36535 AN XY: 74360

African (AFR) AF: 0.722 AC: 29946 AN: 41470

American (AMR) AF: 0.382 AC: 5830 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1371 AN: 3466

East Asian (EAS) AF: 0.149 AC: 773 AN: 5178

South Asian (SAS) AF: 0.462 AC: 2231 AN: 4826

European-Finnish (FIN) AF: 0.347 AC: 3674 AN: 10588

Middle Eastern (MID) AF: 0.462 AC: 135 AN: 292

European-Non Finnish (NFE) AF: 0.448 AC: 30443 AN: 68002

Other (OTH) AF: 0.467 AC: 985 AN: 2110

Alfa AF: 0.455 Hom.: 69773

Bravo AF: 0.506

Asia WGS AF: 0.348 AC: 1214 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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.

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Meckel syndrome, type 8 Benign:3

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joubert syndrome 24 Benign:1

Jul 15, 2021

Genome-Nilou Lab

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	-0.89
CADD	Benign	0.91
DANN	Benign	0.55
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7137946; hg19: chr12-124177289;