rs79037278

Positions:

• chr2-165912511-T-C

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.2322+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00646 in 1,607,380 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (44 hom.)
• Consequence: TTC21B NM_024753.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0004591
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.85

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=-0.52).
• BP6: Variant 2-165912511-T-C is Benign according to our data. Variant chr2-165912511-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 220095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165912511-T-C is described in Lovd as [Benign]. Variant chr2-165912511-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00578 (880/152300) while in subpopulation EAS AF= 0.0243 (126/5178). AF 95% confidence interval is 0.0209. There are 5 homozygotes in gnomad4. There are 474 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.2322+3A>G		splice_donor_region_variant, intron_variant		ENST00000243344.8	NP_079029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.2322+3A>G		splice_donor_region_variant, intron_variant		1	NM_024753.5	ENSP00000243344	P1

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 884 AN: 152182 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0247

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00595

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00732 AC: 1840 AN: 251380 Hom.: 19 AF XY: 0.00688 AC XY: 935 AN XY: 135862

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.0266

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.00583

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.00653 AC: 9497 AN: 1455080 Hom.: 44 Cov.: 29 AF XY: 0.00634 AC XY: 4596 AN XY: 724436

Gnomad4 AFR exome AF: 0.000690

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00291

Gnomad4 EAS exome AF: 0.0223

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.0223

Gnomad4 NFE exome AF: 0.00611

Gnomad4 OTH exome AF: 0.00589

GnomAD4 genome AF: 0.00578 AC: 880 AN: 152300 Hom.: 5 Cov.: 32 AF XY: 0.00636 AC XY: 474 AN XY: 74480

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0243

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0240

Gnomad4 NFE AF: 0.00595

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00567 Hom.: 6

Bravo AF: 0.00430

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.00578

EpiControl AF: 0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TTC21B: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2019	This variant is associated with the following publications: (PMID: 21258341, 31180159) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Nephronophthisis 12 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

Asphyxiating thoracic dystrophy 4;C3151186:Nephronophthisis 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Asphyxiating thoracic dystrophy 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jeune thoracic dystrophy;C0687120:Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Joubert syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.030
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: rs79037278; hg19: chr2-166769021;