2-165874224-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024753.5(TTC21B):c.*531A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 152,046 control chromosomes in the GnomAD database, including 2,283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2283 hom., cov: 32)
  • Exomes 𝑓: 0.16 (9 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTC21B NM_024753.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.638

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-165874224-T-C is Benign according to our data. Variant chr2-165874224-T-C is described in ClinVar as [Benign]. Clinvar id is 331810.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC21B	NM_024753.5	c.*531A>G		3_prime_UTR_variant	29/29	ENST00000243344.8
TTC21B	XM_011511871.4	c.*531A>G		3_prime_UTR_variant	24/24
TTC21B	XM_047445870.1	c.*531A>G		3_prime_UTR_variant	25/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8	c.*531A>G		3_prime_UTR_variant	29/29	1	NM_024753.5	P1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25636 AN: 151928 Hom.: 2278 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.205

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.156 AC: 109 AN: 698 Hom.: 9 Cov.: 0 AF XY: 0.152 AC XY: 75 AN XY: 492

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.0357

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.169 AC: 25657 AN: 152046 Hom.: 2283 Cov.: 32 AF XY: 0.168 AC XY: 12491 AN XY: 74332

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.204

Alfa AF: 0.170 Hom.: 264

Bravo AF: 0.172

Asia WGS AF: 0.166 AC: 577 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Asphyxiating thoracic dystrophy 4 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. -

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	-0.89
Cadd	Benign	4.3
Dann	Benign	0.73

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: rs56115495; hg19: chr2-166730734;