2-165883959-A-G

Variant names:

• chr2-165883959-A-G
• rs115504901
• NM_024753.5:c.3519T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024753.5(TTC21B):​c.3519T>C​(p.Thr1173Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0337 in 1,614,034 control chromosomes in the GnomAD database, including 1,262 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. T1173T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.030 (116 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1146 hom.)
• Consequence: TTC21B NM_024753.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.29

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-165883959-A-G is Benign according to our data. Variant chr2-165883959-A-G is described in ClinVar as [Benign]. Clinvar id is 130655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165883959-A-G is described in Lovd as [Benign]. Variant chr2-165883959-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0296 (4500/152242) while in subpopulation NFE AF= 0.0372 (2530/68010). AF 95% confidence interval is 0.036. There are 116 homozygotes in gnomad4. There are 2347 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 116 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.3519T>C	p.Thr1173Thr	synonymous_variant	Exon 26 of 29	ENST00000243344.8	NP_079029.3
TTC21B	XM_017004967.2	c.3519T>C	p.Thr1173Thr	synonymous_variant	Exon 26 of 28		XP_016860456.1
TTC21B	XM_047445870.1	c.2865T>C	p.Thr955Thr	synonymous_variant	Exon 22 of 25		XP_047301826.1
TTC21B	XM_011511871.4	c.2769T>C	p.Thr923Thr	synonymous_variant	Exon 21 of 24		XP_011510173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.3519T>C	p.Thr1173Thr	synonymous_variant	Exon 26 of 29	1	NM_024753.5	ENSP00000243344.7

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4500 AN: 152124 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.00816

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0372

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0312 AC: 7831 AN: 251180 Hom.: 219 AF XY: 0.0303 AC XY: 4120 AN XY: 135750

Gnomad AFR exome AF: 0.00824

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00350

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0392

Gnomad OTH exome AF: 0.0323

GnomAD4 exome AF: 0.0341 AC: 49890 AN: 1461792 Hom.: 1146 Cov.: 32 AF XY: 0.0331 AC XY: 24055 AN XY: 727206

Gnomad4 AFR exome AF: 0.00762

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00335

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.0368

Gnomad4 OTH exome AF: 0.0283

GnomAD4 genome AF: 0.0296 AC: 4500 AN: 152242 Hom.: 116 Cov.: 32 AF XY: 0.0315 AC XY: 2347 AN XY: 74442

Gnomad4 AFR AF: 0.00816

Gnomad4 AMR AF: 0.0275

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.0372

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0231 Hom.: 19

Bravo AF: 0.0232

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 19, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:3

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Asphyxiating thoracic dystrophy 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis 12 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 17, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.32
DANN	Benign	0.62

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: rs115504901; hg19: chr2-166740469;