rs45467297

Positions:

Variant summary

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

The NM_014844.5(TECPR2):c.2050C>G(p.Leu684Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0443 in 1,613,664 control chromosomes in the GnomAD database, including 1,907 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 136 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1771 hom. )

Consequence

TECPR2
NM_014844.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.443

Variant links:

Genes affected

TECPR2 (HGNC:19957): (tectonin beta-propeller repeat containing 2) The protein encoded by this gene is a member of the tectonin beta-propeller repeat-containing (TECPR) family, and contains both TECPR and tryptophan-aspartic acid repeat (WD repeat) domains. This gene has been implicated in autophagy, as reduced expression levels of this gene have been associated with impaired autophagy. Recessive mutations in this gene have been associated with a hereditary form of spastic paraparesis (HSP). HSP is characterized by progressive spasticity and paralysis of the legs. There is also some evidence linking mutations in this gene with birdshot chorioretinopathy (BSCR), which results in inflammation of the choroid and retina. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

TECPR2 links:

TECPR2 (HGNC:):

TECPR2 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=0.00415799).

BP6

Variant 14-102434867-C-G is Benign according to our data. Variant chr14-102434867-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 380957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102434867-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECPR2	NM_014844.5 linkuse as main transcript	c.2050C>G	p.Leu684Val	missense_variant	9/20	ENST00000359520.12	NP_055659.2	O15040-1
TECPR2	NM_001172631.3 linkuse as main transcript	c.2050C>G	p.Leu684Val	missense_variant	9/17		NP_001166102.1	O15040-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TECPR2	ENST00000359520.12 linkuse as main transcript	c.2050C>G	p.Leu684Val	missense_variant	9/20	1	NM_014844.5	ENSP00000352510.7	O15040-1
TECPR2	ENST00000558678.1 linkuse as main transcript	c.2050C>G	p.Leu684Val	missense_variant	9/17	1		ENSP00000453671.1	O15040-2
TECPR2	ENST00000560060.5 linkuse as main transcript	n.29C>G		non_coding_transcript_exon_variant	1/5	4

Frequencies

GnomAD3 genomes

AF:

0.0334

AC:

5078

AN:

152238

Hom.:

137

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00793

Gnomad AMI

AF:

0.116

Gnomad AMR

AF:

0.0641

Gnomad ASJ

AF:

0.0239

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0518

Gnomad FIN

AF:

0.0293

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0433

Gnomad OTH

AF:

0.0349

GnomAD3 exomes

AF:

0.0438

AC:

10985

AN:

250750

Hom.:

379

AF XY:

0.0430

AC XY:

5835

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.00844

Gnomad AMR exome

AF:

0.0922

Gnomad ASJ exome

AF:

0.0269

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0513

Gnomad FIN exome

AF:

0.0286

Gnomad NFE exome

AF:

0.0434

Gnomad OTH exome

AF:

0.0452

GnomAD4 exome

AF:

0.0454

AC:

66395

AN:

1461308

Hom.:

1771

Cov.:

AF XY:

0.0453

AC XY:

32918

AN XY:

726962

show subpopulations

Gnomad4 AFR exome

AF:

0.00759

Gnomad4 AMR exome

AF:

0.0871

Gnomad4 ASJ exome

AF:

0.0262

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0505

Gnomad4 FIN exome

AF:

0.0310

Gnomad4 NFE exome

AF:

0.0477

Gnomad4 OTH exome

AF:

0.0409

GnomAD4 genome

AF:

0.0333

AC:

5075

AN:

152356

Hom.:

136

Cov.:

AF XY:

0.0331

AC XY:

2466

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00791

Gnomad4 AMR

AF:

0.0640

Gnomad4 ASJ

AF:

0.0239

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0516

Gnomad4 FIN

AF:

0.0293

Gnomad4 NFE

AF:

0.0433

Gnomad4 OTH

AF:

0.0345

Alfa

AF:

0.0384

Hom.:

Bravo

AF:

0.0347

TwinsUK

AF:

0.0504

AC:

187

ALSPAC

AF:

0.0400

AC:

154

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.0413

AC:

355

ExAC

AF:

0.0423

AC:

5142

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0408

EpiControl

AF:

0.0396

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 49

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Jul 11, 2020	This variant has been reported compound heterozygous with the variant of unknown significance NM_014844.4:c.2708C>T, p.(Thr903Met) in a 15 year old girl with muscular hypotonia of the trunk and upper limbs, spastic gait, dysarthria and mild thinning of the corpus callosum in cranial MRI (PMID: 27406698). The variant is paternally inherited. The family is from Italian descent. This missense variant c.2050C>G, p.(Leu684Val) in exon 10/20 of TECPR2 has been reported in ClinVar as benign (380957). In the general population the minor allele frequency is 0.04244 including at least 404 individuals with homozygosity for this variant (gnomAD). Biallelic truncating or missense variants have been described to cause "Spastic paraplegia 49, autosomal recessive" (Oz-Levi et al. Am J Hum Genet. 2012, PMID: 23176824). Multiple in silico-tools predict this variant as benign. Taken together, we classify this variant as benign based on the ACMG recommendations (Richards et al., 2015, PMID 25741868; criteria: BS1 BS2 BP4). -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 27, 2017	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 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	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	May 17, 2017	BS1, BS2, BP1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, is a missense alteration in a gene for which primarily truncating variants are known to cause disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 21, 2021

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.67

CADD

Benign

2.0

DANN

Benign

0.82

DEOGEN2

Benign

0.0057

T;.

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.44

T;T

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.45

N;N

REVEL

Benign

0.014

Sift

Benign

0.21

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.0060

B;.

Vest4

0.064

MPC

0.31

ClinPred

0.000036

GERP RS

1.7

Varity_R

0.022

gMVP

0.15

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

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