chr2-165901879-C-T

Position:

chr2-165901879-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM2PM5BP4_StrongBP6BS1

The NM_024753.5(TTC21B):c.2600G>A(p.Arg867His) variant causes a missense change. The variant allele was found at a frequency of 0.000279 in 1,613,072 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R867C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

TTC21B
NM_024753.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 6.14

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.05013907).

BP6

Variant 2-165901879-C-T is Benign according to our data. Variant chr2-165901879-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261776.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=5}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00142 (215/151328) while in subpopulation AFR AF= 0.00493 (203/41162). AF 95% confidence interval is 0.00438. There are 0 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC21B	NM_024753.5 link	c.2600G>A	p.Arg867His	missense_variant	20/29	ENST00000243344.8	NP_079029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8 link	c.2600G>A	p.Arg867His	missense_variant	20/29	1	NM_024753.5	ENSP00000243344.7		Q7Z4L5-1

Frequencies

GnomAD3 genomes

AF:

0.00142

AC:

215

AN:

151214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00495

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000330

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:

0.0000736

Gnomad OTH

AF:

0.000962

GnomAD3 exomes

AF:

0.000390

AC:

AN:

251350

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00542

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000161

AC:

235

AN:

1461744

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

113

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00472

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.00142

AC:

215

AN:

151328

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

73884

show subpopulations

Gnomad4 AFR

AF:

0.00493

Gnomad4 AMR

AF:

0.000330

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.000952

Alfa

AF:

0.000405

Hom.:

Bravo

AF:

0.00160

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2020	This variant is associated with the following publications: (PMID: 27666822, 21258341) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2019	The TTC21B c.2600G>A; p.Arg867His variant (rs76726265) is reported in the literature in an individual affected with Meckel-Gruber syndrome (Davis 2011), an individual with asphyxiating thoracic dystrophy (Duran 2016), as well as a healthy control (Davis 2011). However, both affected individuals carried additional pathogenic variants that could explain the observed phenotypes (Davis 2011, Duran 2016). Another variant at this codon (p.Arg867Cys) has been reported in an individual with Joubert syndrome (Davis 2011). The p.Arg867His variant is reported in ClinVar (Variation ID: 261776) and is found in the African population with an overall allele frequency of 0.49% (117/24006 alleles) in the Genome Aggregation Database. The arginine at codon 867 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In an in vivo complementation assay of zebrafish ttc21b morphant phenotypes, neither a p.Arg867His variant nor a p.Arg867Cys variant rescued developmental phenotypes as robustly as a wildtype human TTC21B control (Davis 2011). Due to conflicting information, the clinical significance of the p.Arg867His variant is uncertain at this time. References: Davis EE et al. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet. 2011 Mar;43(3):189-96. Duran I et al. Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome. Sci Rep. 2016 Sep 26;6:34232. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 20, 2021	DNA sequence analysis of the TTC21B gene demonstrated a sequence change, c.2600G>A, in exon 20 that results in an amino acid change, p.Arg867His. This sequence change has been described in the gnomAD database with a frequency of 0.53% in the African/African American subpopulation (dbSNP rs76726265). The p.Arg867His change affects a highly conserved amino acid residue located in a domain of the TTC21B protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg867His substitution. This sequence change has been reported in an individual with Meckel-Gruber syndrome and in an individual with asphyxiating thoracic dystrophy (PMID: 21258341, 27666822 ). These individuals, however, also carried a pathogenic variant in another gene that could cause their phenotype. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg867His change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nephronophthisis 12

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Aug 18, 2020	- -

Jeune thoracic dystrophy;C0687120:Nephronophthisis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Asphyxiating thoracic dystrophy 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.026

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.40

MutationAssessor

Pathogenic

2.9

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.41

Sift

Benign

0.035

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.90

MVP

0.51

MPC

0.25

ClinPred

0.15

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.46

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