12-123699822-C-T

Variant names:

• chr12-123699822-C-T
• rs117614122
• NM_024809.5:c.1612+12C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024809.5(TCTN2):​c.1612+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,608,546 control chromosomes in the GnomAD database, including 307 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 0.014 (14 hom., cov: 32)
  • Exomes 𝑓: 0.018 (293 hom.)
• Consequence: TCTN2 NM_024809.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.621

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-123699822-C-T is Benign according to our data. Variant chr12-123699822-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261787.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr12-123699822-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0136 (2077/152230) while in subpopulation NFE AF= 0.0212 (1444/68020). AF 95% confidence interval is 0.0203. There are 14 homozygotes in gnomad4. There are 965 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.1612+12C>T		intron_variant	Intron 14 of 17	ENST00000303372.7	NP_079085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.1612+12C>T		intron_variant	Intron 14 of 17	1	NM_024809.5	ENSP00000304941.5

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2077 AN: 152112 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.00959

GnomAD3 exomes AF: 0.0141 AC: 3545 AN: 250922 Hom.: 42 AF XY: 0.0143 AC XY: 1945 AN XY: 135740

Gnomad AFR exome AF: 0.00371

Gnomad AMR exome AF: 0.00790

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00471

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0181 AC: 26301 AN: 1456316 Hom.: 293 Cov.: 29 AF XY: 0.0178 AC XY: 12921 AN XY: 724822

Gnomad4 AFR exome AF: 0.00288

Gnomad4 AMR exome AF: 0.00827

Gnomad4 ASJ exome AF: 0.0185

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00506

Gnomad4 FIN exome AF: 0.0151

Gnomad4 NFE exome AF: 0.0208

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0136 AC: 2077 AN: 152230 Hom.: 14 Cov.: 32 AF XY: 0.0130 AC XY: 965 AN XY: 74444

Gnomad4 AFR AF: 0.00407

Gnomad4 AMR AF: 0.00962

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.0212

Gnomad4 OTH AF: 0.00949

Alfa AF: 0.00940 Hom.: 4

Bravo AF: 0.0125

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Aug 31, 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

- -

Meckel syndrome, type 8 Uncertain:1

Jan 12, 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:Familial aplasia of the vermis Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 24 Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.39
DANN	Benign	0.61

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: rs117614122; hg19: chr12-124184369;