rs76843552

Variant names:

• chr12-110614414-G-C
• rs76843552
• NM_001082538.3:c.220+12G>C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PVS1_Supporting BP6_Very_Strong BS1 BS2

The NM_001173975.3(TCTN1):​c.3G>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0091 in 1,585,846 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0093 (72 hom.)
• Consequence: TCTN1 NM_001173975.3 start_lost
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.350

Genes affected

TCTN1 (HGNC:26113): (tectonic family member 1) This gene encodes a member of a family of secreted and transmembrane proteins. The orthologous gene in mouse functions downstream of smoothened and rab23 to modulate hedgehog signal transduction. This protein is a component of the tectonic-like complex, which forms a barrier between the ciliary axoneme and the basal body. A mutation in this gene was found in a family with Joubert syndrome-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 123 codons. Genomic position: 110628829. Lost 0.230 part of the original CDS.
• BP6: Variant 12-110614414-G-C is Benign according to our data. Variant chr12-110614414-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 160096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110614414-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00706 (1076/152356) while in subpopulation NFE AF= 0.00941 (640/68030). AF 95% confidence interval is 0.0088. There are 1 homozygotes in gnomad4. There are 521 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 72 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN1	NM_001082538.3	c.220+12G>C		intron_variant	Intron 1 of 14	ENST00000397659.9	NP_001076007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN1	ENST00000397659.9	c.220+12G>C		intron_variant	Intron 1 of 14	1	NM_001082538.3	ENSP00000380779.4
TCTN1	ENST00000551590.5	c.220+12G>C		intron_variant	Intron 1 of 14	1		ENSP00000448735.1
TCTN1	ENST00000397655.7	c.220+12G>C		intron_variant	Intron 1 of 14	1		ENSP00000380775.3
TCTN1	ENST00000495659.6	n.232G>C		non_coding_transcript_exon_variant	Exon 1 of 15	2		ENSP00000436673.2
TCTN1	ENST00000397656.8	n.220+12G>C		intron_variant	Intron 1 of 15	2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.220+12G>C		intron_variant	Intron 1 of 15	5		ENSP00000437196.1

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 1076 AN: 152238 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00897

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00800 AC: 1545 AN: 193076 Hom.: 10 AF XY: 0.00803 AC XY: 846 AN XY: 105418

Gnomad AFR exome AF: 0.00202

Gnomad AMR exome AF: 0.00551

Gnomad ASJ exome AF: 0.00204

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00459

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.00932 AC: 13357 AN: 1433490 Hom.: 72 Cov.: 31 AF XY: 0.00924 AC XY: 6566 AN XY: 710472

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.00569

Gnomad4 ASJ exome AF: 0.00141

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00552

Gnomad4 FIN exome AF: 0.0184

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00658

GnomAD4 genome AF: 0.00706 AC: 1076 AN: 152356 Hom.: 1 Cov.: 31 AF XY: 0.00699 AC XY: 521 AN XY: 74510

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0169

Gnomad4 NFE AF: 0.00941

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00626

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 05, 2017

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. -

not provided Benign:3

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TCTN1: BS1, BS2 -

Aug 23, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 13 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.4
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs76843552; hg19: chr12-111052219;