2-165874238-C-T

Position:

• chr2-165874238-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024753.5(TTC21B):​c.*517G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 151,938 control chromosomes in the GnomAD database, including 2,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2345 hom., cov: 32)
  • Exomes 𝑓: 0.16 (13 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTC21B NM_024753.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.56

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 (BayesDel_noAF=-0.95).
• BP6: Variant 2-165874238-C-T is Benign according to our data. Variant chr2-165874238-C-T is described in ClinVar as [Benign]. Clinvar id is 331811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.*517G>A		3_prime_UTR_variant	29/29	ENST00000243344.8	NP_079029.3
TTC21B	XM_011511871.4	c.*517G>A		3_prime_UTR_variant	24/24		XP_011510173.1
TTC21B	XM_047445870.1	c.*517G>A		3_prime_UTR_variant	25/25		XP_047301826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.*517G>A		3_prime_UTR_variant	29/29	1	NM_024753.5	ENSP00000243344	P1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26112 AN: 151820 Hom.: 2344 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.209

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.158 AC: 133 AN: 842 Hom.: 13 Cov.: 0 AF XY: 0.167 AC XY: 95 AN XY: 570

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.0667

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.172 AC: 26128 AN: 151938 Hom.: 2345 Cov.: 32 AF XY: 0.172 AC XY: 12749 AN XY: 74288

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.273

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.241

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.208

Alfa AF: 0.172 Hom.: 275

Bravo AF: 0.175

Asia WGS AF: 0.185 AC: 643 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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. -

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	-0.95
CADD	Benign	0.34
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: rs77199262; hg19: chr2-166730748;