rs80225158

chr2-165911403-C-Gchr2-165911403-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_024753.5(TTC21B):c.2385G>C(p.Leu795=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,613,778 control chromosomes in the GnomAD database, including 703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L795L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (126 hom., cov: 32)
  • Exomes 𝑓: 0.013 (577 hom.)
• Consequence: TTC21B NM_024753.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.62

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-165911403-C-G is Benign according to our data. Variant chr2-165911403-C-G is described in ClinVar as [Benign]. Clinvar id is 96138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165911403-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC21B	NM_024753.5	c.2385G>C	p.Leu795=	synonymous_variant	18/29	ENST00000243344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8	c.2385G>C	p.Leu795=	synonymous_variant	18/29	1	NM_024753.5	P1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2975 AN: 152064 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.00700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0636

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00670

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0297 AC: 7455 AN: 251202 Hom.: 400 AF XY: 0.0245 AC XY: 3320 AN XY: 135768

Gnomad AFR exome AF: 0.00818

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.0669

Gnomad SAS exome AF: 0.00356

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.00642

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0129 AC: 18887 AN: 1461598 Hom.: 577 Cov.: 31 AF XY: 0.0121 AC XY: 8762 AN XY: 727116

Gnomad4 AFR exome AF: 0.00660

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.00410

Gnomad4 EAS exome AF: 0.0748

Gnomad4 SAS exome AF: 0.00332

Gnomad4 FIN exome AF: 0.0223

Gnomad4 NFE exome AF: 0.00684

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.0195 AC: 2973 AN: 152180 Hom.: 126 Cov.: 32 AF XY: 0.0215 AC XY: 1603 AN XY: 74402

Gnomad4 AFR AF: 0.00696

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.0634

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.0241

Gnomad4 NFE AF: 0.00671

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00605 Hom.: 3

Bravo AF: 0.0258

Asia WGS AF: 0.0280 AC: 98 AN: 3476

EpiCase AF: 0.00676

EpiControl AF: 0.00587

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Asphyxiating thoracic dystrophy 4 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jeune thoracic dystrophy;C0687120:Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 07, 2023

- -

Nephronophthisis 12 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	5.7
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs80225158; hg19: chr2-166767913; COSMIC: COSV99691924; COSMIC: COSV99691924;