rs10176588

Positions:

• chr2-165913610-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024753.5(TTC21B):​c.2175T>C​(p.Phe725=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,609,282 control chromosomes in the GnomAD database, including 111,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8652 hom., cov: 32)
  • Exomes 𝑓: 0.37 (102902 hom.)
• Consequence: TTC21B NM_024753.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.130

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-165913610-A-G is Benign according to our data. Variant chr2-165913610-A-G is described in ClinVar as [Benign]. Clinvar id is 130652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165913610-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC21B	NM_024753.5	c.2175T>C	p.Phe725=	synonymous_variant	16/29	ENST00000243344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8	c.2175T>C	p.Phe725=	synonymous_variant	16/29	1	NM_024753.5	P1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50317 AN: 151786 Hom.: 8653 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.334

GnomAD3 exomes AF: 0.325 AC: 81315 AN: 250544 Hom.: 13962 AF XY: 0.331 AC XY: 44907 AN XY: 135546

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.197

Gnomad SAS exome AF: 0.334

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.371 AC: 540297 AN: 1457378 Hom.: 102902 Cov.: 33 AF XY: 0.370 AC XY: 268180 AN XY: 725274

Gnomad4 AFR exome AF: 0.263

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.194

Gnomad4 SAS exome AF: 0.334

Gnomad4 FIN exome AF: 0.332

Gnomad4 NFE exome AF: 0.391

Gnomad4 OTH exome AF: 0.368

GnomAD4 genome AF: 0.331 AC: 50326 AN: 151904 Hom.: 8652 Cov.: 32 AF XY: 0.327 AC XY: 24290 AN XY: 74270

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.270

Gnomad4 ASJ AF: 0.414

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.325

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.388

Gnomad4 OTH AF: 0.338

Alfa AF: 0.370 Hom.: 20497

Bravo AF: 0.321

Asia WGS AF: 0.280 AC: 972 AN: 3474

EpiCase AF: 0.392

EpiControl AF: 0.384

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Asphyxiating thoracic dystrophy 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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

- -

Nephronophthisis 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.2
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10176588; hg19: chr2-166770120; COSMIC: COSV54627817;