2-165941111-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_024753.5(TTC21B):​c.626C>T​(p.Pro209Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

TTC21B
NM_024753.5 missense

Scores

9
8
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22

Conservation

PhyloP100: 8.08
Variant links:
Genes affected
TTC21B (HGNC:25660): (tetratricopeptide repeat domain 21B) This gene encodes a member of TTC21 family, containing several tetratricopeptide repeat (TPR) domains. This protein is localized to the cilium axoneme, and may play a role in retrograde intraflagellar transport in cilia. Mutations in this gene are associated with various ciliopathies, nephronophthisis 12, and asphyxiating thoracic dystrophy 4. [provided by RefSeq, Oct 2011]
TTC21B-AS1 (HGNC:41115): (TTC21B antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.903
PP5
Variant 2-165941111-G-A is Pathogenic according to our data. Variant chr2-165941111-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165941111-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-165941111-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTC21BNM_024753.5 linkc.626C>T p.Pro209Leu missense_variant Exon 6 of 29 ENST00000243344.8 NP_079029.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTC21BENST00000243344.8 linkc.626C>T p.Pro209Leu missense_variant Exon 6 of 29 1 NM_024753.5 ENSP00000243344.7 Q7Z4L5-1

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152104
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000127
AC:
32
AN:
251118
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135698
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000319
Gnomad ASJ exome
AF:
0.000794
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000881
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000766
AC:
112
AN:
1461614
Hom.:
0
Cov.:
32
AF XY:
0.0000756
AC XY:
55
AN XY:
727108
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000403
Gnomad4 ASJ exome
AF:
0.000689
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000522
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152222
Hom.:
0
Cov.:
33
AF XY:
0.000134
AC XY:
10
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000381
Hom.:
0
Bravo
AF:
0.000144
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:22
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nephronophthisis 12 Pathogenic:6
Mar 01, 2011
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 01, 2015
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 26, 2017
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Previously reported homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS (PMID: 26940125). -

Feb 01, 2020
Molecular Biology Laboratory, Fundació Puigvert
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

-
Genomics And Bioinformatics Analysis Resource, Columbia University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Dec 01, 2022
Eurofins-Biomnis
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:6
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 24, 2019
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 16, 2018
Gharavi Laboratory, Columbia University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 25, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (Huynh Cong et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24876116, 21258341, 29127259, 31456290, 32714622, 33599192, 34426522, 33712733, 31589614, 33226606, 33547761, 33532864, 26940125) -

Nephrotic syndrome Pathogenic:2
Nov 10, 2017
Yale Center for Mendelian Genomics, Yale University
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

May 03, 2018
Sydney Genome Diagnostics, Children's Hospital Westmead
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

This patient is homozygous for a known pathogenic variant, c.626C>T p.(Pro209Leu), in the TTC21B gene. This variant (dbSNP: rs140511594), in the homozygous state, has been previously reported in patients with nephronophthisis and focal segmental glomerulosclerosis (FSGS) (Davis et al 2011 Nat Genet 43:189-196; Cong et al 2014 J Am Soc Nephrol 25:2435-2443; Bullich et al 2017 Nephrol Dial Transplant 32:151-156). Bullich et al 2017 also reported hypertension in some patients homozygous for p.(Pro209Leu). This variant was found in patients of North Africian or Portuguese descent. Functional studies showed the p.Pro209Leu variant partially altered cilia structure, cell migration and cytoskeleton suggesting a hypomorphic allele (Davis et al 2011; Cong et al 2014; Bullich et al 2017). This variant is considered to be pathogenic according to the ACMG guidelines. -

Asphyxiating thoracic dystrophy 4;C3151186:Nephronophthisis 12 Pathogenic:1
Mar 15, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jeune thoracic dystrophy;C0687120:Nephronophthisis Pathogenic:1
Dec 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 209 of the TTC21B protein (p.Pro209Leu). This variant is present in population databases (rs140511594, gnomAD 0.08%). This missense change has been observed in individual(s) with focal segmental glomerulosclerosis and nephronophthisis (PMID: 21258341, 24876116). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30935). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TTC21B protein function. Experimental studies have shown that this missense change affects TTC21B function (PMID: 21258341, 24876116). For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1
May 10, 2021
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PS3, PM3, PP1, PP3 -

TTC21B-related disorder Pathogenic:1
Aug 30, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The TTC21B c.626C>T variant is predicted to result in the amino acid substitution p.Pro209Leu. This variant was reported in the homozygous or compound heterozygous state in multiple individuals with nephronophthisis or focal segmental glomerulosclerosis (FSGS) (Davis et al. 2011. PubMed ID: 21258341; Bullich et al. 2017. PubMed ID: 26940125; Cong et al. 2014. PubMed ID: 24876116). This variant is reported in 0.077% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has been interpreted in ClinVar as pathogenic/likely pathogenic by multiple submitters (https://preview.ncbi.nlm.nih.gov/clinvar/variation/30935/). This variant is interpreted as pathogenic. -

Finnish congenital nephrotic syndrome Pathogenic:1
Nov 21, 2018
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Renal dysplasia and retinal aplasia Pathogenic:1
Jun 23, 2019
Sharon lab, Hadassah-Hebrew University Medical Center
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Retinal dystrophy Pathogenic:1
Sep 22, 2017
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Infantile nephronophthisis Pathogenic:1
Jan 28, 2019
Center of Genomic medicine, Geneva, University Hospital of Geneva
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was identified in composite heterozygosity with another variant in the same gene in a female patient with nephronophtisis, retinopathy and suspected ciliopathy -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
D
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Uncertain
0.35
D
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-6.4
D
REVEL
Pathogenic
0.72
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.043
D
Polyphen
1.0
D
Vest4
0.91
MVP
0.77
MPC
0.23
ClinPred
0.87
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.40
gMVP
0.58

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.

Other links and lift over

dbSNP: rs140511594; hg19: chr2-166797621; COSMIC: COSV99691975; API