NM_014844.5:c.2050C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L684I) has been classified as Uncertain significance.

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

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 49
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

TECPR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 380957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
TECPR2	NM_014844.5 link	c.2050C>G	p.Leu684Val	missense_variant	Exon 9 of 20	ENST00000359520.12	NP_055659.2	O15040-1
TECPR2	NM_001172631.3 link	c.2050C>G	p.Leu684Val	missense_variant	Exon 9 of 17		NP_001166102.1	O15040-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TECPR2	ENST00000359520.12 link	c.2050C>G	p.Leu684Val	missense_variant	Exon 9 of 20	1	NM_014844.5	ENSP00000352510.7	O15040-1
TECPR2	ENST00000558678.1 link	c.2050C>G	p.Leu684Val	missense_variant	Exon 9 of 17	1		ENSP00000453671.1	O15040-2
TECPR2	ENST00000560060.5 link	n.29C>G		non_coding_transcript_exon_variant	Exon 1 of 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

GnomAD2 exomes

AF:

0.0438

AC:

10985

AN:

250750

AF XY:

0.0430

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 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

African (AFR)

AF:

0.00759

AC:

254

AN:

33480

American (AMR)

AF:

0.0871

AC:

3893

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

686

AN:

26136

East Asian (EAS)

AF:

0.000227

AC:

AN:

39700

South Asian (SAS)

AF:

0.0505

AC:

4355

AN:

86258

European-Finnish (FIN)

AF:

0.0310

AC:

1640

AN:

52864

Middle Eastern (MID)

AF:

0.0166

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0477

AC:

52992

AN:

1111994

Other (OTH)

AF:

0.0409

AC:

2470

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

4283

8566

12849

17132

21415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2038

4076

6114

8152

10190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0333

AC:

5075

AN:

152356

Hom.:

136

Cov.:

AF XY:

0.0331

AC XY:

2466

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00791

AC:

329

AN:

41592

American (AMR)

AF:

0.0640

AC:

979

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0516

AC:

249

AN:

4826

European-Finnish (FIN)

AF:

0.0293

AC:

311

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0433

AC:

2943

AN:

68024

Other (OTH)

AF:

0.0345

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

255

509

764

1018

1273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jul 11, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

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). -

Mar 27, 2017

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

May 17, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Apr 22, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Dec 21, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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

PhyloP100

0.44

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

Mutation Taster

=86/14

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over