12-123696502-C-T

Position:

• chr12-123696502-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024809.5(TCTN2):​c.1393+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,610,082 control chromosomes in the GnomAD database, including 113,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10303 hom., cov: 32)
  • Exomes 𝑓: 0.37 (102748 hom.)
• Consequence: TCTN2 NM_024809.5 splice_region, intron
• Scores: Splicing: ADA: 0.0008338
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.105

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-123696502-C-T is Benign according to our data. Variant chr12-123696502-C-T is described in ClinVar as [Benign]. Clinvar id is 126285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123696502-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.1393+7C>T		splice_region_variant, intron_variant		ENST00000303372.7	NP_079085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.1393+7C>T		splice_region_variant, intron_variant		1	NM_024809.5	ENSP00000304941.5

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54595 AN: 151928 Hom.: 10296 Cov.: 32

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.0563

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.352

GnomAD3 exomes AF: 0.318 AC: 79926 AN: 251408 Hom.: 14076 AF XY: 0.325 AC XY: 44119 AN XY: 135874

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.195

Gnomad ASJ exome AF: 0.319

Gnomad EAS exome AF: 0.0554

Gnomad SAS exome AF: 0.328

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.368 AC: 536063 AN: 1458036 Hom.: 102748 Cov.: 31 AF XY: 0.367 AC XY: 266139 AN XY: 725540

Gnomad4 AFR exome AF: 0.423

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.317

Gnomad4 EAS exome AF: 0.0470

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.392

Gnomad4 OTH exome AF: 0.354

GnomAD4 genome AF: 0.359 AC: 54635 AN: 152046 Hom.: 10303 Cov.: 32 AF XY: 0.354 AC XY: 26314 AN XY: 74320

Gnomad4 AFR AF: 0.412

Gnomad4 AMR AF: 0.270

Gnomad4 ASJ AF: 0.324

Gnomad4 EAS AF: 0.0562

Gnomad4 SAS AF: 0.311

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.383

Gnomad4 OTH AF: 0.347

Alfa AF: 0.343 Hom.: 3147

Bravo AF: 0.359

Asia WGS AF: 0.185 AC: 646 AN: 3478

EpiCase AF: 0.387

EpiControl AF: 0.386

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 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. -

Meckel syndrome, type 8 Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

- -

Joubert syndrome 24 Benign:1

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 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	-0.80
CADD	Benign	2.0
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00083
dbscSNV1_RF	Benign	0.080
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: rs7298440; hg19: chr12-124181049; COSMIC: COSV57632846;