2-165890935-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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). Synonymous variant affecting the same amino acid position (i.e. L1002L) has been classified as Likely benign.

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

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

nephronophthisis 12
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
asphyxiating thoracic dystrophy 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nephronophthisis 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TTC21B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 195777.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TTC21B	NM_024753.5 link	c.3004C>G	p.Leu1002Val	missense_variant	Exon 23 of 29	ENST00000243344.8	NP_079029.3
TTC21B	XM_017004967.2 link	c.3004C>G	p.Leu1002Val	missense_variant	Exon 23 of 28		XP_016860456.1
TTC21B	XM_047445870.1 link	c.2350C>G	p.Leu784Val	missense_variant	Exon 19 of 25		XP_047301826.1
TTC21B	XM_011511871.4 link	c.2254C>G	p.Leu752Val	missense_variant	Exon 18 of 24		XP_011510173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8 link	c.3004C>G	p.Leu1002Val	missense_variant	Exon 23 of 29	1	NM_024753.5	ENSP00000243344.7

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

GnomAD2 exomes

AF:

0.00529

AC:

1324

AN:

250162

AF XY:

0.00533

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 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

African (AFR)

AF:

0.00105

AC:

AN:

33448

American (AMR)

AF:

0.00329

AC:

147

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00391

AC:

102

AN:

26118

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39602

South Asian (SAS)

AF:

0.00253

AC:

218

AN:

86236

European-Finnish (FIN)

AF:

0.00212

AC:

113

AN:

53388

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00999

AC:

11106

AN:

1111256

Other (OTH)

AF:

0.00782

AC:

472

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

595

1190

1786

2381

2976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

438

876

1314

1752

2190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00513

AC:

780

AN:

152112

Hom.:

Cov.:

AF XY:

0.00448

AC XY:

333

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00205

AC:

AN:

41514

American (AMR)

AF:

0.00282

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00896

AC:

609

AN:

67974

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jun 15, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21258341, 26940125)

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTC21B: BS1, BS2

Aug 16, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1Benign:2

Jan 12, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jeune thoracic dystrophy;C0687120:Nephronophthisis

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asphyxiating thoracic dystrophy 4

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Chronic kidney disease

Benign:1

May 28, 2020

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

PP3, BP6, BS1

Nephronophthisis 12

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joubert syndrome 1

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Connective tissue disorder

Benign:1

Oct 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

3.3

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.24

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.026

Vest4

0.66

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

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over