rs77804131

chr12-123690539-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_024809.5(TCTN2):c.898C>T(p.Leu300=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,614,162 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 32)
  • Exomes 𝑓: 0.017 (305 hom.)
• Consequence: TCTN2 NM_024809.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0540

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-123690539-C-T is Benign according to our data. Variant chr12-123690539-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 126295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123690539-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.054 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0111 (1688/152318) while in subpopulation SAS AF= 0.0306 (148/4830). AF 95% confidence interval is 0.0266. There are 14 homozygotes in gnomad4. There are 833 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCTN2	NM_024809.5	c.898C>T	p.Leu300=	synonymous_variant	8/18	ENST00000303372.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN2	ENST00000303372.7	c.898C>T	p.Leu300=	synonymous_variant	8/18	1	NM_024809.5	P4

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1685 AN: 152200 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00996

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.0143 AC: 3601 AN: 251478 Hom.: 51 AF XY: 0.0163 AC XY: 2219 AN XY: 135920

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0373

Gnomad FIN exome AF: 0.00813

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0174 AC: 25398 AN: 1461844 Hom.: 305 Cov.: 32 AF XY: 0.0181 AC XY: 13181 AN XY: 727228

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.00606

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0389

Gnomad4 FIN exome AF: 0.00863

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0111 AC: 1688 AN: 152318 Hom.: 14 Cov.: 32 AF XY: 0.0112 AC XY: 833 AN XY: 74478

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.00994

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0306

Gnomad4 FIN AF: 0.00669

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.0140 Hom.: 14

Bravo AF: 0.00971

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.0184

EpiControl AF: 0.0168

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Joubert syndrome 24 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Meckel syndrome, type 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	7.2
Dann	Benign	0.64

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: rs77804131; hg19: chr12-124175086; COSMIC: COSV57635066; COSMIC: COSV57635066;