12-110645031-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001082538.3(TCTN1):​c.1396G>T​(p.Gly466Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0232 in 1,614,174 control chromosomes in the GnomAD database, including 579 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 37 hom., cov: 32)
Exomes 𝑓: 0.024 ( 542 hom. )

Consequence

TCTN1
NM_001082538.3 missense

Scores

7
11

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.63
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]
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]

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=0.0045828223).
BP6
Variant 12-110645031-G-T is Benign according to our data. Variant chr12-110645031-G-T is described in ClinVar as [Benign]. Clinvar id is 160095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110645031-G-T is described in Lovd as [Benign]. Variant chr12-110645031-G-T is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TCTN1NM_001082538.3 linkc.1396G>T p.Gly466Cys missense_variant Exon 12 of 15 ENST00000397659.9 NP_001076007.1 Q2MV58-2B4DIB9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TCTN1ENST00000397659.9 linkc.1396G>T p.Gly466Cys missense_variant Exon 12 of 15 1 NM_001082538.3 ENSP00000380779.4 Q2MV58-2
TCTN1ENST00000551590.5 linkc.1396G>T p.Gly466Cys missense_variant Exon 12 of 15 1 ENSP00000448735.1 Q2MV58-1
TCTN1ENST00000397655.7 linkc.1354G>T p.Gly452Cys missense_variant Exon 12 of 15 1 ENSP00000380775.3 Q2MV58-3
TCTN1ENST00000397656.8 linkn.*1029G>T non_coding_transcript_exon_variant Exon 13 of 16 2 ENSP00000380776.4 J3KPW2
TCTN1ENST00000480648.5 linkn.*672G>T non_coding_transcript_exon_variant Exon 13 of 16 5 ENSP00000437196.1 E9PNE4
TCTN1ENST00000495659.6 linkn.*1154G>T non_coding_transcript_exon_variant Exon 12 of 15 2 ENSP00000436673.2 E9PIB8
TCTN1ENST00000397656.8 linkn.*1029G>T 3_prime_UTR_variant Exon 13 of 16 2 ENSP00000380776.4 J3KPW2
TCTN1ENST00000480648.5 linkn.*672G>T 3_prime_UTR_variant Exon 13 of 16 5 ENSP00000437196.1 E9PNE4
TCTN1ENST00000495659.6 linkn.*1154G>T 3_prime_UTR_variant Exon 12 of 15 2 ENSP00000436673.2 E9PIB8

Frequencies

GnomAD3 genomes
AF:
0.0166
AC:
2532
AN:
152174
Hom.:
36
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00401
Gnomad AMI
AF:
0.0132
Gnomad AMR
AF:
0.0184
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.0146
Gnomad SAS
AF:
0.0569
Gnomad FIN
AF:
0.00867
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0236
Gnomad OTH
AF:
0.00862
GnomAD3 exomes
AF:
0.0214
AC:
5338
AN:
249560
Hom.:
106
AF XY:
0.0228
AC XY:
3086
AN XY:
135398
show subpopulations
Gnomad AFR exome
AF:
0.00368
Gnomad AMR exome
AF:
0.0141
Gnomad ASJ exome
AF:
0.00209
Gnomad EAS exome
AF:
0.0118
Gnomad SAS exome
AF:
0.0522
Gnomad FIN exome
AF:
0.0110
Gnomad NFE exome
AF:
0.0230
Gnomad OTH exome
AF:
0.0195
GnomAD4 exome
AF:
0.0239
AC:
34883
AN:
1461882
Hom.:
542
Cov.:
30
AF XY:
0.0244
AC XY:
17762
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00370
Gnomad4 AMR exome
AF:
0.0143
Gnomad4 ASJ exome
AF:
0.00230
Gnomad4 EAS exome
AF:
0.0106
Gnomad4 SAS exome
AF:
0.0505
Gnomad4 FIN exome
AF:
0.0114
Gnomad4 NFE exome
AF:
0.0247
Gnomad4 OTH exome
AF:
0.0189
GnomAD4 genome
AF:
0.0166
AC:
2535
AN:
152292
Hom.:
37
Cov.:
32
AF XY:
0.0176
AC XY:
1310
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00399
Gnomad4 AMR
AF:
0.0184
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.0137
Gnomad4 SAS
AF:
0.0565
Gnomad4 FIN
AF:
0.00867
Gnomad4 NFE
AF:
0.0236
Gnomad4 OTH
AF:
0.0133
Alfa
AF:
0.0157
Hom.:
10
Bravo
AF:
0.0161
TwinsUK
AF:
0.0272
AC:
101
ALSPAC
AF:
0.0272
AC:
105
ESP6500AA
AF:
0.00397
AC:
15
ESP6500EA
AF:
0.0211
AC:
173
ExAC
AF:
0.0229
AC:
2769
Asia WGS
AF:
0.0290
AC:
102
AN:
3478
EpiCase
AF:
0.0187
EpiControl
AF:
0.0181

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
-
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

- -

Mar 29, 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. -

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

- -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Joubert syndrome 13 Benign:1
Jan 12, 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
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.18
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
.;T;.;.;.
Eigen
Benign
-0.023
Eigen_PC
Benign
0.0073
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.82
T;T;T;T;T
MetaRNN
Benign
0.0046
T;T;T;T;T
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Uncertain
2.2
.;M;.;M;.
PrimateAI
Benign
0.29
T
PROVEAN
Uncertain
-3.0
.;D;D;D;.
REVEL
Uncertain
0.43
Sift
Uncertain
0.014
.;D;D;D;.
Sift4G
Benign
0.088
T;T;T;T;T
Polyphen
1.0, 1.0
.;D;D;D;.
Vest4
0.10
MPC
0.70
ClinPred
0.014
T
GERP RS
3.5
Varity_R
0.16
gMVP
0.53

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

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

Other links and lift over

dbSNP: rs118096349; hg19: chr12-111082836; API