rs6750044

Positions:

• chr2-165917461-G-A

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.1695C>T​(p.Tyr565=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,610,158 control chromosomes in the GnomAD database, including 112,556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9205 hom., cov: 32)
  • Exomes 𝑓: 0.37 (103351 hom.)
• Consequence: TTC21B NM_024753.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.08

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=-0.51).
• BP6: Variant 2-165917461-G-A is Benign according to our data. Variant chr2-165917461-G-A is described in ClinVar as [Benign]. Clinvar id is 130650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165917461-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.08 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	Protein	UniProt
TTC21B	NM_024753.5	c.1695C>T	p.Tyr565=	synonymous_variant	14/29	ENST00000243344.8	NP_079029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.1695C>T	p.Tyr565=	synonymous_variant	14/29	1	NM_024753.5	ENSP00000243344	P1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52206 AN: 151864 Hom.: 9205 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.342

GnomAD3 exomes AF: 0.328 AC: 82165 AN: 250882 Hom.: 14149 AF XY: 0.333 AC XY: 45202 AN XY: 135618

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.407

Gnomad EAS exome AF: 0.197

Gnomad SAS exome AF: 0.334

Gnomad FIN exome AF: 0.326

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.337

GnomAD4 exome AF: 0.372 AC: 542382 AN: 1458176 Hom.: 103351 Cov.: 34 AF XY: 0.371 AC XY: 269032 AN XY: 725616

Gnomad4 AFR exome AF: 0.304

Gnomad4 AMR exome AF: 0.222

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: 0.371

GnomAD4 genome AF: 0.344 AC: 52224 AN: 151982 Hom.: 9205 Cov.: 32 AF XY: 0.338 AC XY: 25155 AN XY: 74316

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.276

Gnomad4 ASJ AF: 0.414

Gnomad4 EAS AF: 0.194

Gnomad4 SAS AF: 0.326

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.388

Gnomad4 OTH AF: 0.345

Alfa AF: 0.369 Hom.: 13905

Bravo AF: 0.335

Asia WGS AF: 0.284 AC: 988 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.384

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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. -

Asphyxiating thoracic dystrophy 4 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Jeune thoracic dystrophy;C0687120:Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.6
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs6750044; hg19: chr2-166773971; COSMIC: COSV54627832;