rs117896500

Positions:

chr12-110628782-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001082538.3(TCTN1):c.488C>A(p.Ser163Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000573 in 1,604,468 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 9 hom. )

Consequence

TCTN1
NM_001082538.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.52

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009011716).

BP6

Variant 12-110628782-C-A is Benign according to our data. Variant chr12-110628782-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 197179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110628782-C-A is described in Lovd as [Benign]. Variant chr12-110628782-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000742 (113/152250) while in subpopulation EAS AF= 0.00656 (34/5182). AF 95% confidence interval is 0.00483. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCTN1	NM_001082538.3 linkuse as main transcript	c.488C>A	p.Ser163Tyr	missense_variant	4/15	ENST00000397659.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN1	ENST00000397659.9 linkuse as main transcript	c.488C>A	p.Ser163Tyr	missense_variant	4/15	1	NM_001082538.3	A1	Q2MV58-2

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00655

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00246

AC:

610

AN:

248234

Hom.:

AF XY:

0.00189

AC XY:

255

AN XY:

134790

show subpopulations

Gnomad AFR exome

AF:

0.000713

Gnomad AMR exome

AF:

0.0136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00640

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.000555

AC:

806

AN:

1452218

Hom.:

Cov.:

AF XY:

0.000487

AC XY:

352

AN XY:

723160

show subpopulations

Gnomad4 AFR exome

AF:

0.000571

Gnomad4 AMR exome

AF:

0.0122

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00450

Gnomad4 SAS exome

AF:

0.000360

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000109

Gnomad4 OTH exome

AF:

0.000316

GnomAD4 genome

AF:

0.000742

AC:

113

AN:

152250

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00656

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000470

Hom.:

Bravo

AF:

0.00151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000557

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00197

AC:

238

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2018	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. -

Joubert syndrome 13

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 19, 2022	- -
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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

.;.;T;.;.;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.82

T;T;T;T;T;T

MetaRNN

Benign

0.0090

T;T;T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

2.0

.;.;M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.27

.;.;N;N;N;.

REVEL

Uncertain

0.41

Sift

Benign

1.0

.;.;T;T;T;.

Sift4G

Uncertain

0.013

D;T;T;T;T;T

Polyphen

1.0

D;.;D;D;D;.

Vest4

0.17

MVP

0.83

MPC

0.41

ClinPred

0.025

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.050

gMVP

0.74

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