chr2-165953687-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024753.5(TTC21B):c.19A>G(p.Lys7Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 794,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0013 ( 0 hom. )

Consequence

TTC21B
NM_024753.5 missense, splice_region

Scores

Splicing: ADA: 0.004587

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.359

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016642302).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024753.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	NM_024753.5	MANE Select	c.19A>G	p.Lys7Glu	missense splice_region	Exon 1 of 29	NP_079029.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTC21B	ENST00000243344.8	TSL:1 MANE Select	c.19A>G	p.Lys7Glu	missense splice_region	Exon 1 of 29	ENSP00000243344.7
TTC21B	ENST00000464374.5	TSL:1	n.59A>G		splice_region non_coding_transcript_exon	Exon 1 of 11
TTC21B	ENST00000679840.1		c.19A>G	p.Lys7Glu	missense splice_region	Exon 1 of 27	ENSP00000505248.1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

AN:

71062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000375

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00219

Gnomad OTH

AF:

0.00103

GnomAD2 exomes

AF:

0.000661

AC:

AN:

65090

AF XY:

0.000759

show subpopulations

Gnomad AFR exome

AF:

0.000602

Gnomad AMR exome

AF:

0.000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.00161

GnomAD4 exome

AF:

0.00127

AC:

918

AN:

723314

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

415

AN XY:

358398

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

13812

American (AMR)

AF:

0.000334

AC:

AN:

14972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12892

East Asian (EAS)

AF:

0.00

AC:

AN:

25410

South Asian (SAS)

AF:

0.0000214

AC:

AN:

46790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3184

European-Non Finnish (NFE)

AF:

0.00159

AC:

869

AN:

544858

Other (OTH)

AF:

0.00129

AC:

AN:

31734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

112

167

223

279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<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:

0.00118

AC:

AN:

71104

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

34790

show subpopulations

African (AFR)

AF:

0.000374

AC:

AN:

16034

American (AMR)

AF:

0.000274

AC:

AN:

7290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1816

East Asian (EAS)

AF:

0.00

AC:

AN:

2872

South Asian (SAS)

AF:

0.00

AC:

AN:

2430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

130

European-Non Finnish (NFE)

AF:

0.00219

AC:

AN:

34262

Other (OTH)

AF:

0.00102

AC:

AN:

982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000434

Hom.:

Bravo

AF:

0.000506

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000437

AC:

ExAC

AF:

0.000194

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Mar 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TTC21B c.19A>G, p.Lys7Glu variant (rs375721812), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 331843). This variant is found in the European population with an allele frequency of .16% (52/32148 alleles) in the Genome Aggregation Database. The lysine at position 7 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.188). Although evidence suggests that p.Lys7Glu may be a rare benign variant, there is insufficient information to determine its clinical significance with certainty.

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 05, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Jeune thoracic dystrophy;C0687120:Nephronophthisis

Uncertain:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 7 of the TTC21B protein (p.Lys7Glu). This variant is present in population databases (rs375721812, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TTC21B-related conditions. ClinVar contains an entry for this variant (Variation ID: 331843). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Asphyxiating thoracic dystrophy 4

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Nephronophthisis 12

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTC21B-related disorder

Uncertain:1

Sep 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TTC21B c.19A>G variant is predicted to result in the amino acid substitution p.Lys7Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.16% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.063

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.3

PhyloP100

0.36

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.35

REVEL

Benign

0.19

Sift

Benign

0.22

Sift4G

Benign

1.0

Polyphen

0.025

Vest4

0.43

MVP

0.22

MPC

0.037

ClinPred

0.039

GERP RS

3.4

PromoterAI

0.012

Neutral

(source)

Varity_R

0.21

gMVP

0.13

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0046

dbscSNV1_RF

Benign

0.080

SpliceAI score (max)

0.080

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over