2-165941136-C-T

Position:

chr2-165941136-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.742

Variant links:

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 links:

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

TTC21B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.601G>A	p.Val201Met	missense_variant	6/29	ENST00000243344.8	NP_079029.3
TTC21B-AS1	NR_038983.1 linkuse as main transcript	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 linkuse as main transcript	c.601G>A	p.Val201Met	missense_variant	6/29	1	NM_024753.5	ENSP00000243344	P1	Q7Z4L5-1
TTC21B-AS1	ENST00000440322.5 linkuse as main transcript	n.221-6061C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.624

AC:

94748

AN:

151902

Hom.:

29867

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.626

AC XY:

455210

AN XY:

727010

show subpopulations

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.:

AF XY:

0.630

AC XY:

46780

AN XY:

74294

show subpopulations

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

LINK: link

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

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

0.064

Eigen_PC

Benign

-0.045

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0000022

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

0.11

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.1

REVEL

Benign

0.23

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0070

Polyphen

0.99

Vest4

0.21

MPC

0.21

ClinPred

0.037

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over