rs73418153

Variant names:

• chr12-123688159-A-G
• rs73418153
• NM_024809.5:c.873A>G

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.873A>G​(p.Ala291Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,610,976 control chromosomes in the GnomAD database, including 1,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (450 hom., cov: 32)
  • Exomes 𝑓: 0.022 (739 hom.)
• Consequence: TCTN2 NM_024809.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.58

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=-0.79).
• BP6: Variant 12-123688159-A-G is Benign according to our data. Variant chr12-123688159-A-G is described in ClinVar as [Benign]. Clinvar id is 126292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123688159-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.873A>G	p.Ala291Ala	synonymous_variant	Exon 7 of 18	ENST00000303372.7	NP_079085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.873A>G	p.Ala291Ala	synonymous_variant	Exon 7 of 18	1	NM_024809.5	ENSP00000304941.5

Frequencies

GnomAD3 genomes AF: 0.0547 AC: 8313 AN: 151964 Hom.: 452 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0747

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00693

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.00663

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0297 AC: 7469 AN: 251070 Hom.: 250 AF XY: 0.0280 AC XY: 3800 AN XY: 135678

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.0492

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.00696

Gnomad SAS exome AF: 0.0385

Gnomad FIN exome AF: 0.00809

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0222 AC: 32434 AN: 1458902 Hom.: 739 Cov.: 35 AF XY: 0.0224 AC XY: 16262 AN XY: 725838

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.0532

Gnomad4 ASJ exome AF: 0.0226

Gnomad4 EAS exome AF: 0.00439

Gnomad4 SAS exome AF: 0.0414

Gnomad4 FIN exome AF: 0.00862

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0276

GnomAD4 genome AF: 0.0548 AC: 8330 AN: 152074 Hom.: 450 Cov.: 32 AF XY: 0.0541 AC XY: 4025 AN XY: 74338

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.0746

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00695

Gnomad4 SAS AF: 0.0345

Gnomad4 FIN AF: 0.00663

Gnomad4 NFE AF: 0.0171

Gnomad4 OTH AF: 0.0398

Alfa AF: 0.0312 Hom.: 105

Bravo AF: 0.0616

Asia WGS AF: 0.0320 AC: 112 AN: 3478

EpiCase AF: 0.0189

EpiControl AF: 0.0175

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 04, 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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 24 Benign:1

Jan 13, 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. -

Meckel syndrome, type 8 Benign:1

Jan 13, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.020
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: rs73418153; hg19: chr12-124172706;