rs146496725

Positions:

chr2-165890935-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024753.5(TTC21B):c.3004C>G(p.Leu1002Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00805 in 1,612,974 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0051 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0084 ( 70 hom. )

Consequence

TTC21B
NM_024753.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 3.29

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:

TTC21B (HGNC:):

TTC21B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009657979).

BP6

Variant 2-165890935-G-C is Benign according to our data. Variant chr2-165890935-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195777.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=1, Benign=4}. Variant chr2-165890935-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00513 (780/152112) while in subpopulation NFE AF= 0.00896 (609/67974). AF 95% confidence interval is 0.00837. There are 4 homozygotes in gnomad4. There are 333 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC21B	NM_024753.5 linkuse as main transcript	c.3004C>G	p.Leu1002Val	missense_variant	23/29	ENST00000243344.8	NP_079029.3
TTC21B	XM_017004967.2 linkuse as main transcript	c.3004C>G	p.Leu1002Val	missense_variant	23/28		XP_016860456.1	A0A7P0TB61
TTC21B	XM_047445870.1 linkuse as main transcript	c.2350C>G	p.Leu784Val	missense_variant	19/25		XP_047301826.1
TTC21B	XM_011511871.4 linkuse as main transcript	c.2254C>G	p.Leu752Val	missense_variant	18/24		XP_011510173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8 linkuse as main transcript	c.3004C>G	p.Leu1002Val	missense_variant	23/29	1	NM_024753.5	ENSP00000243344.7		Q7Z4L5-1

Frequencies

GnomAD3 genomes

AF:

0.00513

AC:

780

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00896

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00529

AC:

1324

AN:

250162

Hom.:

AF XY:

0.00533

AC XY:

721

AN XY:

135398

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.00378

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00265

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.00889

Gnomad OTH exome

AF:

0.00427

GnomAD4 exome

AF:

0.00836

AC:

12211

AN:

1460862

Hom.:

Cov.:

AF XY:

0.00818

AC XY:

5946

AN XY:

726738

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00329

Gnomad4 ASJ exome

AF:

0.00391

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00253

Gnomad4 FIN exome

AF:

0.00212

Gnomad4 NFE exome

AF:

0.00999

Gnomad4 OTH exome

AF:

0.00782

GnomAD4 genome

AF:

0.00513

AC:

780

AN:

152112

Hom.:

Cov.:

AF XY:

0.00448

AC XY:

333

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00205

Gnomad4 AMR

AF:

0.00282

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00896

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00827

Hom.:

Bravo

AF:

0.00529

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.00557

AC:

676

Asia WGS

AF:

0.000867

AC:

AN:

3476

EpiCase

AF:

0.00965

EpiControl

AF:

0.00753

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2020	This variant is associated with the following publications: (PMID: 21258341, 26940125) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 16, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TTC21B: BS2 -

not specified

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Has been reported in 5 individuals with MKS, BBS, or NPHP (Davis 2011). All were heterozygotes only, except for one individual with BBS who also had a frameshift variant in this gene. Led to partial rescue of function in zebrafish knockdown studies and mislocalized protein in photoreceptors in retinal electroporation assays. Also identified in 1/356 control chromosomes. 0.9% freq in Eur chr in ExAC. -

Asphyxiating thoracic dystrophy 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jeune thoracic dystrophy;C0687120:Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Chronic kidney disease

Benign:1

Likely benign, criteria provided, single submitter

research

Cavalleri Lab, Royal College of Surgeons in Ireland

May 28, 2020

PP3, BP6, BS1 -

Nephronophthisis 12

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Joubert syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.027

MetaRNN

Benign

0.0097

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.24

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.026

Polyphen

0.96

Vest4

0.66

MVP

0.45

MPC

0.14

ClinPred

0.030

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.39

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