rs2163649

Positions:

chr2-165924648-G-A

Variant summary

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

The NM_024753.5(TTC21B):c.1417C>T(p.Leu473Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,613,684 control chromosomes in the GnomAD database, including 699 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 124 hom., cov: 32)

Exomes 𝑓: 0.013 ( 575 hom. )

Consequence

TTC21B
NM_024753.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.66

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 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=0.0019389987).

BP6

Variant 2-165924648-G-A is Benign according to our data. Variant chr2-165924648-G-A is described in ClinVar as [Benign]. Clinvar id is 96137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165924648-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC21B	NM_024753.5 linkuse as main transcript	c.1417C>T	p.Leu473Phe	missense_variant	12/29	ENST00000243344.8	NP_079029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8 linkuse as main transcript	c.1417C>T	p.Leu473Phe	missense_variant	12/29	1	NM_024753.5	ENSP00000243344	P1	Q7Z4L5-1

Frequencies

GnomAD3 genomes

AF:

0.0184

AC:

2800

AN:

152188

Hom.:

123

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.0640

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.0239

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00672

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0293

AC:

7363

AN:

251288

Hom.:

396

AF XY:

0.0243

AC XY:

3295

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.00456

Gnomad EAS exome

AF:

0.0667

Gnomad SAS exome

AF:

0.00376

Gnomad FIN exome

AF:

0.0231

Gnomad NFE exome

AF:

0.00640

Gnomad OTH exome

AF:

0.0220

GnomAD4 exome

AF:

0.0128

AC:

18719

AN:

1461378

Hom.:

575

Cov.:

AF XY:

0.0120

AC XY:

8703

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.129

Gnomad4 ASJ exome

AF:

0.00410

Gnomad4 EAS exome

AF:

0.0748

Gnomad4 SAS exome

AF:

0.00344

Gnomad4 FIN exome

AF:

0.0223

Gnomad4 NFE exome

AF:

0.00684

Gnomad4 OTH exome

AF:

0.0117

GnomAD4 genome

AF:

0.0184

AC:

2799

AN:

152306

Hom.:

124

Cov.:

AF XY:

0.0204

AC XY:

1522

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00298

Gnomad4 AMR

AF:

0.102

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.0638

Gnomad4 SAS

AF:

0.00497

Gnomad4 FIN

AF:

0.0239

Gnomad4 NFE

AF:

0.00672

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.00993

Hom.:

Bravo

AF:

0.0243

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.0237

AC:

2877

Asia WGS

AF:

0.0290

AC:

AN:

3476

EpiCase

AF:

0.00677

EpiControl

AF:

0.00581

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2016	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. -

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Jeune thoracic dystrophy;C0687120:Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Asphyxiating thoracic dystrophy 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephronophthisis 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

0.93

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.11

Sift

Benign

0.059

Sift4G

Benign

0.12

Polyphen

0.0030

Vest4

0.030

MPC

0.032

ClinPred

0.0078

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.095

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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