2-165874774-C-T

Position:

• chr2-165874774-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_024753.5(TTC21B):​c.3932G>A​(p.Arg1311His) variant causes a missense change. The variant allele was found at a frequency of 0.000914 in 1,613,496 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1311G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (2 hom.)
• Consequence: TTC21B NM_024753.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 5.84

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11024344).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.3932G>A	p.Arg1311His	missense_variant	29/29	ENST00000243344.8	NP_079029.3
TTC21B	XM_047445870.1	c.3278G>A	p.Arg1093His	missense_variant	25/25		XP_047301826.1
TTC21B	XM_011511871.4	c.3182G>A	p.Arg1061His	missense_variant	24/24		XP_011510173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.3932G>A	p.Arg1311His	missense_variant	29/29	1	NM_024753.5	ENSP00000243344	P1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00104

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000554 AC: 139 AN: 251086 Hom.: 0 AF XY: 0.000538 AC XY: 73 AN XY: 135678

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000951 AC: 1390 AN: 1461322 Hom.: 2 Cov.: 30 AF XY: 0.000937 AC XY: 681 AN XY: 726996

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.000498 AC XY: 37 AN XY: 74336

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.000604

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000568 AC: 69

EpiCase AF: 0.000982

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 22, 2022	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2021	Reported in heterozygous state in a patient with renal and genital anomalies (Hilger et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26294094, 21258341) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 25, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TTC21B: PM2, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	The TTC21B c.3932G>A; p.Arg1311His variant (rs139327086) is reported in the literature in an individual with renal and genital anomalies (Hilger 2015). This variant is also reported in ClinVar (Variation ID: 219735). It is observed in the general population with an overall allele frequency of 0.05% (151/282482 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.25). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Hilger AC et al. Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association. Hum Mutat. 2015 Dec;36(12):1150-4. PMID: 26294094. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 20, 2015	- -

Asphyxiating thoracic dystrophy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jeune thoracic dystrophy;C0687120:Nephronophthisis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1311 of the TTC21B protein (p.Arg1311His). This variant is present in population databases (rs139327086, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinically-diverse ciliopathies (PMID: 21258341). ClinVar contains an entry for this variant (Variation ID: 219735). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TTC21B protein function. 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

Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

TTC21B-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2024

The TTC21B c.3932G>A variant is predicted to result in the amino acid substitution p.Arg1311His. This variant was reported in the heterozygous state in an individual with renal and genital anomalies (Hilger et al. 2015. PubMed ID: 26294094). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. 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	0.29
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.25
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.032	D
Polyphen		0.74	P
Vest4		0.33
MVP		0.52
MPC		0.057
ClinPred		0.18	T
GERP RS		5.6
Varity_R		0.18
gMVP		0.51

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

Other links and lift over

dbSNP: rs139327086; hg19: chr2-166731284;