rs146496725

chr2-165890935-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024753.5(TTC21B):c.3004C>G(p.Leu1002Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00805 in 1,612,974 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1002L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0051 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (70 hom.)
• Consequence: TTC21B NM_024753.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 3.29

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009657979).
• BP6: Variant 2-165890935-G-C is Benign according to our data. Variant chr2-165890935-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195777.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=8, Uncertain_significance=1}. Variant chr2-165890935-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00513 (780/152112) while in subpopulation NFE AF= 0.00896 (609/67974). AF 95% confidence interval is 0.00837. There are 4 homozygotes in gnomad4. There are 333 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC21B	NM_024753.5	c.3004C>G	p.Leu1002Val	missense_variant	23/29	ENST00000243344.8
TTC21B	XM_017004967.2	c.3004C>G	p.Leu1002Val	missense_variant	23/28
TTC21B	XM_047445870.1	c.2350C>G	p.Leu784Val	missense_variant	19/25
TTC21B	XM_011511871.4	c.2254C>G	p.Leu752Val	missense_variant	18/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8	c.3004C>G	p.Leu1002Val	missense_variant	23/29	1	NM_024753.5	P1

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 780 AN: 151994 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00896

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00529 AC: 1324 AN: 250162 Hom.: 3 AF XY: 0.00533 AC XY: 721 AN XY: 135398

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00889

Gnomad OTH exome AF: 0.00427

GnomAD4 exome AF: 0.00836 AC: 12211 AN: 1460862 Hom.: 70 Cov.: 31 AF XY: 0.00818 AC XY: 5946 AN XY: 726738

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00391

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00253

Gnomad4 FIN exome AF: 0.00212

Gnomad4 NFE exome AF: 0.00999

Gnomad4 OTH exome AF: 0.00782

GnomAD4 genome AF: 0.00513 AC: 780 AN: 152112 Hom.: 4 Cov.: 32 AF XY: 0.00448 AC XY: 333 AN XY: 74382

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00896

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00827 Hom.: 5

Bravo AF: 0.00529

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.00557 AC: 676

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.00965

EpiControl AF: 0.00753

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TTC21B: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2020	This variant is associated with the following publications: (PMID: 21258341, 26940125) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 16, 2017	- -

not specified Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Has been reported in 5 individuals with MKS, BBS, or NPHP (Davis 2011). All were heterozygotes only, except for one individual with BBS who also had a frameshift variant in this gene. Led to partial rescue of function in zebrafish knockdown studies and mislocalized protein in photoreceptors in retinal electroporation assays. Also identified in 1/356 control chromosomes. 0.9% freq in Eur chr in ExAC. -

Jeune thoracic dystrophy;C0687120:Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Asphyxiating thoracic dystrophy 4 Benign:1

Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Chronic kidney disease Benign:1

Likely benign, criteria provided, single submitter

research

Cavalleri Lab, Royal College of Surgeons in Ireland

May 28, 2020

PP3, BP6, BS1 -

Nephronophthisis 12 Benign:1

Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Joubert syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.026	D
Polyphen		0.96	D
Vest4		0.66
MVP		0.45
MPC		0.14
ClinPred		0.030	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.39

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: rs146496725; hg19: chr2-166747445; COSMIC: COSV99074759; COSMIC: COSV99074759;