rs75714509

Positions:

chr12-110642292-A-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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

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:

TCTN1 (HGNC:):

TCTN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 72 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCTN1	NM_001082538.3 linkuse as main transcript	c.1234A>G	p.Ile412Val	missense_variant	11/15	ENST00000397659.9	NP_001076007.1	Q2MV58-2B4DIB9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TCTN1	ENST00000397659.9 linkuse as main transcript	c.1234A>G	p.Ile412Val	missense_variant	11/15	1	NM_001082538.3	ENSP00000380779.4	Q2MV58-2
TCTN1	ENST00000551590.5 linkuse as main transcript	c.1234A>G	p.Ile412Val	missense_variant	11/15	1		ENSP00000448735.1	Q2MV58-1
TCTN1	ENST00000397655.7 linkuse as main transcript	c.1192A>G	p.Ile398Val	missense_variant	11/15	1		ENSP00000380775.3	Q2MV58-3
TCTN1	ENST00000397656.8 linkuse as main transcript	n.*867A>G		non_coding_transcript_exon_variant	12/16	2		ENSP00000380776.4	J3KPW2
TCTN1	ENST00000480648.5 linkuse as main transcript	n.*510A>G		non_coding_transcript_exon_variant	12/16	5		ENSP00000437196.1	E9PNE4
TCTN1	ENST00000495659.6 linkuse as main transcript	n.*992A>G		non_coding_transcript_exon_variant	11/15	2		ENSP00000436673.2	E9PIB8
TCTN1	ENST00000397656.8 linkuse as main transcript	n.*867A>G		3_prime_UTR_variant	12/16	2		ENSP00000380776.4	J3KPW2
TCTN1	ENST00000480648.5 linkuse as main transcript	n.*510A>G		3_prime_UTR_variant	12/16	5		ENSP00000437196.1	E9PNE4
TCTN1	ENST00000495659.6 linkuse as main transcript	n.*992A>G		3_prime_UTR_variant	11/15	2		ENSP00000436673.2	E9PIB8

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

GnomAD3 exomes

AF:

0.00759

AC:

1894

AN:

249562

Hom.:

AF XY:

0.00768

AC XY:

1040

AN XY:

135398

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 SAS exome

AF:

0.00454

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

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.00552

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00546

Gnomad4 FIN exome

AF:

0.0184

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00674

GnomAD4 genome

AF:

0.00710

AC:

1082

AN:

152306

Hom.:

Cov.:

AF XY:

0.00706

AC XY:

526

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.00889

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00436

Gnomad4 FIN

AF:

0.0170

Gnomad4 NFE

AF:

0.00944

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00842

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 21, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2017	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	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TCTN1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 23, 2017	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Joubert syndrome 13

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over