rs151318349

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_024809.5(TCTN2):ā€‹c.776A>Gā€‹(p.Gln259Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,614,132 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00069 ( 0 hom., cov: 32)
Exomes š‘“: 0.0012 ( 1 hom. )

Consequence

TCTN2
NM_024809.5 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.0340
Variant links:
Genes affected
TCTN2 (HGNC:25774): (tectonic family member 2) This gene encodes a type I membrane protein that belongs to the tectonic family. Studies in mice suggest that this protein may be involved in hedgehog signaling, and essential for ciliogenesis. Mutations in this gene are associated with Meckel syndrome type 8. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.010862678).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000689 (105/152342) while in subpopulation NFE AF= 0.00119 (81/68034). AF 95% confidence interval is 0.000981. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TCTN2NM_024809.5 linkuse as main transcriptc.776A>G p.Gln259Arg missense_variant 7/18 ENST00000303372.7 NP_079085.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TCTN2ENST00000303372.7 linkuse as main transcriptc.776A>G p.Gln259Arg missense_variant 7/181 NM_024809.5 ENSP00000304941 P4Q96GX1-1

Frequencies

GnomAD3 genomes
AF:
0.000690
AC:
105
AN:
152224
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000386
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00119
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000553
AC:
139
AN:
251462
Hom.:
0
AF XY:
0.000596
AC XY:
81
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00113
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00116
AC:
1689
AN:
1461790
Hom.:
1
Cov.:
35
AF XY:
0.00113
AC XY:
824
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.00144
Gnomad4 OTH exome
AF:
0.00111
GnomAD4 genome
AF:
0.000689
AC:
105
AN:
152342
Hom.:
0
Cov.:
32
AF XY:
0.000550
AC XY:
41
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.000385
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00119
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00106
Hom.:
0
Bravo
AF:
0.000725
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00130
AC:
5
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000552
AC:
67
EpiCase
AF:
0.00169
EpiControl
AF:
0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 259 of the TCTN2 protein (p.Gln259Arg). This variant is present in population databases (rs151318349, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TCTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 307553). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TCTN2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Joubert syndrome 24 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Meckel syndrome, type 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 18, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
0.95
DANN
Benign
0.65
DEOGEN2
Benign
0.27
.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.30
N
LIST_S2
Benign
0.31
T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.011
T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
1.6
.;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.77
N;N
REVEL
Benign
0.10
Sift
Benign
0.83
T;T
Sift4G
Benign
0.69
T;T
Polyphen
0.014
.;B
Vest4
0.053
MVP
0.52
MPC
0.15
ClinPred
0.0065
T
GERP RS
0.47
Varity_R
0.041
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs151318349; hg19: chr12-124172609; API