rs2273906

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.1315C>T(p.Pro439Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,612,818 control chromosomes in the GnomAD database, including 1,112 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P439L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.042 ( 157 hom., cov: 32)

Exomes 𝑓: 0.034 ( 955 hom. )

Consequence

TECPR2
NM_014844.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.911

Publications

11 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=0.0022470057).

BP6

Variant 14-102432026-C-T is Benign according to our data. Variant chr14-102432026-C-T is described in ClinVar as Benign. ClinVar VariationId is 380927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECPR2	NM_014844.5 link	c.1315C>T	p.Pro439Ser	missense_variant	Exon 8 of 20	ENST00000359520.12	NP_055659.2	O15040-1
TECPR2	NM_001172631.3 link	c.1315C>T	p.Pro439Ser	missense_variant	Exon 8 of 17		NP_001166102.1	O15040-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECPR2	ENST00000359520.12 link	c.1315C>T	p.Pro439Ser	missense_variant	Exon 8 of 20	1	NM_014844.5	ENSP00000352510.7		O15040-1
TECPR2	ENST00000558678.1 link	c.1315C>T	p.Pro439Ser	missense_variant	Exon 8 of 17	1		ENSP00000453671.1		O15040-2

Frequencies

GnomAD3 genomes

AF:

0.0417

AC:

6344

AN:

152192

Hom.:

157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0571

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0454

Gnomad ASJ

AF:

0.0455

Gnomad EAS

AF:

0.0343

Gnomad SAS

AF:

0.0424

Gnomad FIN

AF:

0.0406

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0313

Gnomad OTH

AF:

0.0521

GnomAD2 exomes

AF:

0.0390

AC:

9512

AN:

244072

AF XY:

0.0378

show subpopulations

Gnomad AFR exome

AF:

0.0584

Gnomad AMR exome

AF:

0.0627

Gnomad ASJ exome

AF:

0.0488

Gnomad EAS exome

AF:

0.0288

Gnomad FIN exome

AF:

0.0375

Gnomad NFE exome

AF:

0.0303

Gnomad OTH exome

AF:

0.0402

GnomAD4 exome

AF:

0.0336

AC:

49130

AN:

1460508

Hom.:

955

Cov.:

AF XY:

0.0334

AC XY:

24277

AN XY:

726556

show subpopulations

African (AFR)

AF:

0.0545

AC:

1826

AN:

33476

American (AMR)

AF:

0.0604

AC:

2699

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.0470

AC:

1227

AN:

26128

East Asian (EAS)

AF:

0.0401

AC:

1593

AN:

39696

South Asian (SAS)

AF:

0.0380

AC:

3279

AN:

86226

European-Finnish (FIN)

AF:

0.0392

AC:

2051

AN:

52316

Middle Eastern (MID)

AF:

0.0530

AC:

305

AN:

5758

European-Non Finnish (NFE)

AF:

0.0306

AC:

34004

AN:

1111862

Other (OTH)

AF:

0.0355

AC:

2146

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

2788

5575

8363

11150

13938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1348

2696

4044

5392

6740

<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:

0.0417

AC:

6350

AN:

152310

Hom.:

157

Cov.:

AF XY:

0.0416

AC XY:

3099

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0571

AC:

2372

AN:

41560

American (AMR)

AF:

0.0454

AC:

694

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0455

AC:

158

AN:

3472

East Asian (EAS)

AF:

0.0342

AC:

177

AN:

5178

South Asian (SAS)

AF:

0.0425

AC:

205

AN:

4826

European-Finnish (FIN)

AF:

0.0406

AC:

431

AN:

10620

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0313

AC:

2130

AN:

68034

Other (OTH)

AF:

0.0525

AC:

111

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

300

600

900

1200

1500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0345

Hom.:

277

Bravo

AF:

0.0432

TwinsUK

AF:

0.0297

AC:

110

ALSPAC

AF:

0.0301

AC:

116

ESP6500AA

AF:

0.0491

AC:

203

ESP6500EA

AF:

0.0269

AC:

221

ExAC

AF:

0.0372

AC:

4479

Asia WGS

AF:

0.0480

AC:

165

AN:

3478

EpiCase

AF:

0.0334

EpiControl

AF:

0.0306

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Apr 15, 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. -

Hereditary spastic paraplegia 49

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Jan 15, 2022

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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.1

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.010

T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.2

M;M

PhyloP100

0.91

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.086

Sift

Benign

0.41

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.036

B;.

Vest4

0.020

MPC

0.31

ClinPred

0.023

GERP RS

4.5

Varity_R

0.038

gMVP

0.26

Mutation Taster

=97/3

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