rs1432273

Positions:

• chr2-165941136-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.601G>A​(p.Val201Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 1,613,424 control chromosomes in the GnomAD database, including 316,920 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29894 hom., cov: 32)
  • Exomes 𝑓: 0.62 (287026 hom.)
• Consequence: TTC21B NM_024753.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.742

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]

TTC21B-AS1 (HGNC:41115): (TTC21B antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2303832E-6).
• BP6: Variant 2-165941136-C-T is Benign according to our data. Variant chr2-165941136-C-T is described in ClinVar as [Benign]. Clinvar id is 130657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165941136-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.601G>A	p.Val201Met	missense_variant	6/29	ENST00000243344.8	NP_079029.3
TTC21B-AS1	NR_038983.1	n.277-6061C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.601G>A	p.Val201Met	missense_variant	6/29	1	NM_024753.5	ENSP00000243344	P1
TTC21B-AS1	ENST00000440322.5	n.221-6061C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94748 AN: 151902 Hom.: 29867 Cov.: 32

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.713

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.636

GnomAD3 exomes AF: 0.664 AC: 166664 AN: 250996 Hom.: 56128 AF XY: 0.660 AC XY: 89565 AN XY: 135620

Gnomad AFR exome AF: 0.577

Gnomad AMR exome AF: 0.783

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.804

Gnomad SAS exome AF: 0.666

Gnomad FIN exome AF: 0.674

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.659

GnomAD4 exome AF: 0.624 AC: 912423 AN: 1461404 Hom.: 287026 Cov.: 50 AF XY: 0.626 AC XY: 455210 AN XY: 727010

Gnomad4 AFR exome AF: 0.579

Gnomad4 AMR exome AF: 0.773

Gnomad4 ASJ exome AF: 0.590

Gnomad4 EAS exome AF: 0.806

Gnomad4 SAS exome AF: 0.665

Gnomad4 FIN exome AF: 0.668

Gnomad4 NFE exome AF: 0.608

Gnomad4 OTH exome AF: 0.622

GnomAD4 genome AF: 0.624 AC: 94830 AN: 152020 Hom.: 29894 Cov.: 32 AF XY: 0.630 AC XY: 46780 AN XY: 74294

Gnomad4 AFR AF: 0.575

Gnomad4 AMR AF: 0.714

Gnomad4 ASJ AF: 0.587

Gnomad4 EAS AF: 0.806

Gnomad4 SAS AF: 0.674

Gnomad4 FIN AF: 0.666

Gnomad4 NFE AF: 0.612

Gnomad4 OTH AF: 0.633

Alfa AF: 0.623 Hom.: 62275

Bravo AF: 0.628

TwinsUK AF: 0.597 AC: 2212

ALSPAC AF: 0.605 AC: 2331

ESP6500AA AF: 0.586 AC: 2580

ESP6500EA AF: 0.610 AC: 5250

ExAC AF: 0.657 AC: 79723

Asia WGS AF: 0.707 AC: 2460 AN: 3478

EpiCase AF: 0.607

EpiControl AF: 0.616

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Asphyxiating thoracic dystrophy 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
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. -

Jeune thoracic dystrophy;C0687120:Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.064
Eigen_PC	Benign	-0.045
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0000022	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	0.11	P
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.21
MPC		0.21
ClinPred		0.037	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1432273; hg19: chr2-166797646;