2-165941072-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024753.5(TTC21B):c.665A>T(p.Gln222Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00216 in 1,613,962 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 39 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 41 hom. )

Consequence

TTC21B
NM_024753.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 4.04

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-AS1 (HGNC:41115): (TTC21B antisense RNA 1)

TTC21B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0083556175).

BP6

Variant 2-165941072-T-A is Benign according to our data. Variant chr2-165941072-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 130658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165941072-T-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1819/152300) while in subpopulation AFR AF = 0.0415 (1726/41552). AF 95% confidence interval is 0.0399. There are 39 homozygotes in GnomAd4. There are 832 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC21B	NM_024753.5 link	c.665A>T	p.Gln222Leu	missense_variant	Exon 6 of 29	ENST00000243344.8	NP_079029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8 link	c.665A>T	p.Gln222Leu	missense_variant	Exon 6 of 29	1	NM_024753.5	ENSP00000243344.7		Q7Z4L5-1

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1817

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0416

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00299

AC:

752

AN:

251252

AF XY:

0.00207

show subpopulations

Gnomad AFR exome

AF:

0.0403

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00114

AC:

1661

AN:

1461662

Hom.:

Cov.:

AF XY:

0.000959

AC XY:

697

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.0398

AC:

1331

AN:

33466

Gnomad4 AMR exome

AF:

0.00266

AC:

119

AN:

44692

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26126

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39684

Gnomad4 SAS exome

AF:

0.0000348

AC:

AN:

86254

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53414

Gnomad4 NFE exome

AF:

0.0000513

AC:

AN:

1111868

Gnomad4 Remaining exome

AF:

0.00242

AC:

146

AN:

60390

Heterozygous variant carriers

176

263

351

439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.0119

AC:

1819

AN:

152300

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

832

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0415

AC:

0.0415383

AN:

0.0415383

Gnomad4 AMR

AF:

0.00490

AC:

0.00490324

AN:

0.00490324

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000207

AC:

0.000207211

AN:

0.000207211

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000294

AC:

0.0000294014

AN:

0.0000294014

Gnomad4 OTH

AF:

0.00663

AC:

0.00662879

AN:

0.00662879

Heterozygous variant carriers

175

263

350

438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000737

Hom.:

Bravo

AF:

0.0139

ESP6500AA

AF:

0.0388

AC:

171

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00369

AC:

448

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 20, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 04, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jun 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTC21B: BP4, BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Asphyxiating thoracic dystrophy 4;C3151186:Nephronophthisis 12

Benign:1

Oct 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Asphyxiating thoracic dystrophy 4

Benign:1

Apr 28, 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. -

Jeune thoracic dystrophy;C0687120:Nephronophthisis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephronophthisis 12

Benign:1

Apr 28, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Connective tissue disorder

Benign:1

Aug 01, 2019

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

0.14

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.15

Eigen

Benign

-0.078

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0084

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.75

REVEL

Benign

0.087

Sift

Benign

0.68

Sift4G

Benign

0.66

Polyphen

0.034

Vest4

0.28

MVP

0.35

MPC

0.031

ClinPred

0.0099

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.42

Mutation Taster

=83/17

polymorphism

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