2-165873650-C-A

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.*1105G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 151,918 control chromosomes in the GnomAD database, including 5,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (5150 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: TTC21B NM_024753.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.364

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=-0.81).
• BP6: Variant 2-165873650-C-A is Benign according to our data. Variant chr2-165873650-C-A is described in ClinVar as [Benign]. Clinvar id is 331798.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC21B	NM_024753.5	c.*1105G>T		3_prime_UTR_variant	29/29	ENST00000243344.8
TTC21B	XM_011511871.4	c.*1105G>T		3_prime_UTR_variant	24/24
TTC21B	XM_047445870.1	c.*1105G>T		3_prime_UTR_variant	25/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8	c.*1105G>T		3_prime_UTR_variant	29/29	1	NM_024753.5	P1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36266 AN: 151800 Hom.: 5148 Cov.: 32

Gnomad AFR AF: 0.0864

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.289

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.239 AC: 36270 AN: 151918 Hom.: 5150 Cov.: 32 AF XY: 0.236 AC XY: 17544 AN XY: 74236

Gnomad4 AFR AF: 0.0862

Gnomad4 AMR AF: 0.258

Gnomad4 ASJ AF: 0.387

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.287

Alfa AF: 0.275 Hom.: 795

Bravo AF: 0.233

Asia WGS AF: 0.185 AC: 645 AN: 3478

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 12, 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 12, 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	-0.81
Cadd	Benign	0.94
Dann	Benign	0.76

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: rs6756388; hg19: chr2-166730160;