rs375721812

Positions:

chr2-165953687-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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. 15/23 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

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC21B	NM_024753.5 linkuse as main transcript	c.19A>G	p.Lys7Glu	missense_variant, splice_region_variant	1/29	ENST00000243344.8	NP_079029.3
TTC21B	XM_017004967.2 linkuse as main transcript	c.19A>G	p.Lys7Glu	missense_variant, splice_region_variant	1/28		XP_016860456.1	A0A7P0TB61
TTC21B	XM_006712761.2 linkuse as main transcript	c.19A>G	p.Lys7Glu	missense_variant, splice_region_variant	1/23		XP_006712824.1	A0A7P0TA66
TTC21B	XM_011511872.3 linkuse as main transcript	c.19A>G	p.Lys7Glu	missense_variant, splice_region_variant	1/21		XP_011510174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8 linkuse as main transcript	c.19A>G	p.Lys7Glu	missense_variant, splice_region_variant	1/29	1	NM_024753.5	ENSP00000243344.7		Q7Z4L5-1

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

GnomAD3 exomes

AF:

0.000661

AC:

AN:

65090

Hom.:

AF XY:

0.000759

AC XY:

AN XY:

34266

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 SAS 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

Gnomad4 AFR exome

AF:

0.000145

Gnomad4 AMR exome

AF:

0.000334

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000214

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00159

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.00118

AC:

AN:

71104

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

34790

show subpopulations

Gnomad4 AFR

AF:

0.000374

Gnomad4 AMR

AF:

0.000274

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00219

Gnomad4 OTH

AF:

0.00102

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

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 21, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2023	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 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Asphyxiating thoracic dystrophy 4

Uncertain:1

Uncertain significance, 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, 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. -

Jeune thoracic dystrophy;C0687120:Nephronophthisis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

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. -

Nephronophthisis 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

TTC21B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2024

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

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

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

Varity_R

0.21

gMVP

0.13

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

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