chr12-123694870-T-C

Position:

• chr12-123694870-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.320

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 126283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123694870-T-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.1128T>C	p.Pro376Pro	synonymous_variant	10/18	ENST00000303372.7	NP_079085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.1128T>C	p.Pro376Pro	synonymous_variant	10/18	1	NM_024809.5	ENSP00000304941.5

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80470 AN: 151964 Hom.: 24113 Cov.: 32

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

GnomAD3 exomes AF: 0.424 AC: 106367 AN: 251142 Hom.: 25248 AF XY: 0.427 AC XY: 57985 AN XY: 135840

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 SAS exome AF: 0.487

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.: 34 AF XY: 0.450 AC XY: 326406 AN XY: 725976

Gnomad4 AFR exome AF: 0.841

Gnomad4 AMR exome AF: 0.292

Gnomad4 ASJ exome AF: 0.396

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.492

Gnomad4 FIN exome AF: 0.356

Gnomad4 NFE exome AF: 0.457

Gnomad4 OTH exome AF: 0.454

GnomAD4 genome AF: 0.530 AC: 80579 AN: 152082 Hom.: 24168 Cov.: 32 AF XY: 0.521 AC XY: 38724 AN XY: 74350

Gnomad4 AFR AF: 0.822

Gnomad4 AMR AF: 0.399

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.463

Gnomad4 FIN AF: 0.347

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.495

Alfa AF: 0.467 Hom.: 24302

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

Submissions by phenotype

Meckel syndrome, type 8 Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.6
DANN	Benign	0.55

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

LitVar

Other links and lift over

dbSNP: rs7966867; hg19: chr12-124179417; COSMIC: COSV57631977; COSMIC: COSV57631977;