rs75714509

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001082538.3(TCTN1):c.1234A>G(p.Ile412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00908 in 1,614,188 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I412T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0071 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0093 ( 72 hom. )

Consequence

TCTN1
NM_001082538.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0910

Publications

10 publications found

Variant links:

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]

TCTN1 links:

HVCN1 (HGNC:28240): (hydrogen voltage gated channel 1) This gene encodes a voltage-gated protein channel protein expressed more highly in certain cells of the immune system. Phagocytic cells produce superoxide anions which require this channel protein, and in B cells this same process facilitates antibody production. This same channel protein, however, can also regulate functions in other cells including spermatozoa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

HVCN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039714277).

BP6

Variant 12-110642292-A-G is Benign according to our data. Variant chr12-110642292-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0071 (1082/152306) while in subpopulation NFE AF = 0.00944 (642/68026). AF 95% confidence interval is 0.00883. There are 1 homozygotes in GnomAd4. There are 526 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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 link	c.1234A>G	p.Ile412Val	missense_variant	Exon 11 of 15	ENST00000397659.9	NP_001076007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TCTN1	ENST00000397659.9 link	c.1234A>G	p.Ile412Val	missense_variant	Exon 11 of 15	1	NM_001082538.3	ENSP00000380779.4
TCTN1	ENST00000551590.5 link	c.1234A>G	p.Ile412Val	missense_variant	Exon 11 of 15	1		ENSP00000448735.1
TCTN1	ENST00000397655.7 link	c.1192A>G	p.Ile398Val	missense_variant	Exon 11 of 15	1		ENSP00000380775.3
TCTN1	ENST00000397656.8 link	n.*867A>G		non_coding_transcript_exon_variant	Exon 12 of 16	2		ENSP00000380776.4
TCTN1	ENST00000480648.5 link	n.*510A>G		non_coding_transcript_exon_variant	Exon 12 of 16	5		ENSP00000437196.1
TCTN1	ENST00000495659.6 link	n.*992A>G		non_coding_transcript_exon_variant	Exon 11 of 15	2		ENSP00000436673.2
TCTN1	ENST00000397656.8 link	n.*867A>G		3_prime_UTR_variant	Exon 12 of 16	2		ENSP00000380776.4
TCTN1	ENST00000480648.5 link	n.*510A>G		3_prime_UTR_variant	Exon 12 of 16	5		ENSP00000437196.1
TCTN1	ENST00000495659.6 link	n.*992A>G		3_prime_UTR_variant	Exon 11 of 15	2		ENSP00000436673.2

Frequencies

GnomAD3 genomes

AF:

0.00711

AC:

1082

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00896

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0170

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00944

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00759

AC:

1894

AN:

249562

AF XY:

0.00768

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.00518

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0192

Gnomad NFE exome

AF:

0.00931

Gnomad OTH exome

AF:

0.0102

GnomAD4 exome

AF:

0.00929

AC:

13577

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00920

AC XY:

6693

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

33480

American (AMR)

AF:

0.00552

AC:

247

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00546

AC:

471

AN:

86256

European-Finnish (FIN)

AF:

0.0184

AC:

984

AN:

53418

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0102

AC:

11330

AN:

1112006

Other (OTH)

AF:

0.00674

AC:

407

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

782

1564

2347

3129

3911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

434

868

1302

1736

2170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00710

AC:

1082

AN:

152306

Hom.:

Cov.:

AF XY:

0.00706

AC XY:

526

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

41566

American (AMR)

AF:

0.00889

AC:

136

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00436

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0170

AC:

180

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00944

AC:

642

AN:

68026

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

110

165

220

275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00825

Hom.:

Bravo

AF:

0.00627

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00186

AC:

ESP6500EA

AF:

0.00864

AC:

ExAC

AF:

0.00738

AC:

892

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00812

EpiControl

AF:

0.00901

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 21, 2013

Eurofins Ntd Llc (ga)

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

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

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TCTN1: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

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:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

1.9

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.073

.;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.76

T;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.74

.;N;.;N

PhyloP100

-0.091

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.36

.;N;N;N

REVEL

Benign

0.073

Sift

Benign

0.39

.;T;T;T

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.0010, 0.0090

.;B;B;B

Vest4

0.072

MVP

0.13

MPC

0.17

ClinPred

0.00056

GERP RS

-3.8

Varity_R

0.024

gMVP

0.38

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over