12-123686991-C-G

Variant names:

• chr12-123686991-C-G
• rs149430216
• NM_024809.5:c.720C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_024809.5(TCTN2):​c.720C>G​(p.Pro240Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,614,160 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (27 hom.)
• Consequence: TCTN2 NM_024809.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: -1.02
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 12-123686991-C-G is Benign according to our data. Variant chr12-123686991-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198261.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00278 (423/152268) while in subpopulation NFE AF = 0.00482 (328/68040). AF 95% confidence interval is 0.00439. There are 4 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.720C>G	p.Pro240Pro	synonymous_variant	Exon 6 of 18	ENST00000303372.7	NP_079085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.720C>G	p.Pro240Pro	synonymous_variant	Exon 6 of 18	1	NM_024809.5	ENSP00000304941.5

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 424 AN: 152150 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00483

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00262 AC: 658 AN: 251484 AF XY: 0.00247

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00470

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00511 AC: 7477 AN: 1461892 Hom.: 27 Cov.: 33 AF XY: 0.00489 AC XY: 3555 AN XY: 727248

African (AFR) AF: 0.00137 AC: 46 AN: 33480

American (AMR) AF: 0.00244 AC: 109 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00631 AC: 7021 AN: 1112010

Other (OTH) AF: 0.00432 AC: 261 AN: 60396

GnomAD4 genome AF: 0.00278 AC: 423 AN: 152268 Hom.: 4 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74448

African (AFR) AF: 0.00130 AC: 54 AN: 41554

American (AMR) AF: 0.00196 AC: 30 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00482 AC: 328 AN: 68040

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00308

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00545

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TCTN2: BP4, BP7, BS2 -

Nov 08, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Sep 22, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 24 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Meckel syndrome, type 8 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome Benign:1

Jan 20, 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	-0.69
CADD	Benign	0.58
DANN	Benign	0.59
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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: rs149430216; hg19: chr12-124171538;