NM_024753.5:c.724G>A

Variant names:

• chr2-165933044-C-T
• rs74447004
• NM_024753.5:c.724G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024753.5(TTC21B):​c.724G>A​(p.Asp242Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00474 in 1,612,510 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (30 hom.)
• Consequence: TTC21B NM_024753.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.26

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005027771).
• BP6: Variant 2-165933044-C-T is Benign according to our data. Variant chr2-165933044-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165933044-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00355 (541/152270) while in subpopulation NFE AF= 0.00569 (387/68022). AF 95% confidence interval is 0.00522. There are 2 homozygotes in gnomad4. There are 232 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.724G>A	p.Asp242Asn	missense_variant	Exon 7 of 29	ENST00000243344.8	NP_079029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.724G>A	p.Asp242Asn	missense_variant	Exon 7 of 29	1	NM_024753.5	ENSP00000243344.7

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 540 AN: 152152 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00570

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00415 AC: 1042 AN: 250952 Hom.: 5 AF XY: 0.00426 AC XY: 578 AN XY: 135630

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.000882

Gnomad NFE exome AF: 0.00628

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00486 AC: 7104 AN: 1460240 Hom.: 30 Cov.: 30 AF XY: 0.00483 AC XY: 3510 AN XY: 726344

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.00119

Gnomad4 NFE exome AF: 0.00546

Gnomad4 OTH exome AF: 0.00477

GnomAD4 genome AF: 0.00355 AC: 541 AN: 152270 Hom.: 2 Cov.: 32 AF XY: 0.00312 AC XY: 232 AN XY: 74454

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00569

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00465 Hom.: 2

Bravo AF: 0.00400

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00432 AC: 524

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Mar 05, 2019

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 03, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21258341, 26874042) -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTC21B: BP4, BS2 -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Asphyxiating thoracic dystrophy 4 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jeune thoracic dystrophy;C0687120:Nephronophthisis Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis 12 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.063
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.079
Sift	Benign	0.16	T
Sift4G	Benign	0.32	T
Polyphen		0.058	B
Vest4		0.36
MVP		0.30
MPC		0.036
ClinPred		0.025	T
GERP RS		4.2
Varity_R		0.19
gMVP		0.52

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: rs74447004; hg19: chr2-166789554;