rs140757802

chr2-165915325-G-Achr2-165915325-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_024753.5(TTC21B):c.2014C>T(p.Arg672Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R672P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: TTC21B NM_024753.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:2
• Conservation: PhyloP100: 1.83

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14573875).
• BP6: Variant 2-165915325-G-A is Benign according to our data. Variant chr2-165915325-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261770.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC21B	NM_024753.5	c.2014C>T	p.Arg672Trp	missense_variant	15/29	ENST00000243344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8	c.2014C>T	p.Arg672Trp	missense_variant	15/29	1	NM_024753.5	P1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251370 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135848

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000732 AC: 107 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.0000825 AC XY: 60 AN XY: 727204

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74430

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000808 Hom.: 0

Bravo AF: 0.000525

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:1 Uncertain:1

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Uncertain significance, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2023

Identified in individual with asphyxiating thoracic dystrophy; however, additional variants in other genes were also identified (Zhang et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29068549) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Jeune thoracic dystrophy;C0687120:Nephronophthisis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.26
Sift	Benign	0.048	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.56
MVP		0.47
MPC		0.089
ClinPred		0.016	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.36

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: rs140757802; hg19: chr2-166771835;