NM_014844.5:c.1471G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_014844.5(TECPR2):c.1471G>A(p.Glu491Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000973 in 1,388,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E491E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

TECPR2
NM_014844.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.91

Publications

2 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2321487).

BP6

Variant 14-102434288-G-A is Benign according to our data. Variant chr14-102434288-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240923.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECPR2	NM_014844.5 link	c.1471G>A	p.Glu491Lys	missense_variant	Exon 9 of 20	ENST00000359520.12	NP_055659.2	O15040-1
TECPR2	NM_001172631.3 link	c.1471G>A	p.Glu491Lys	missense_variant	Exon 9 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.1471G>A	p.Glu491Lys	missense_variant	Exon 9 of 20	1	NM_014844.5	ENSP00000352510.7		O15040-1
TECPR2	ENST00000558678.1 link	c.1471G>A	p.Glu491Lys	missense_variant	Exon 9 of 17	1		ENSP00000453671.1		O15040-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000144

AC:

AN:

152736

AF XY:

0.000210

show subpopulations

Gnomad AFR exome

AF:

0.0000742

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000104

AC:

129

AN:

1236006

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

594928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27964

American (AMR)

AF:

0.00

AC:

AN:

22390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17136

East Asian (EAS)

AF:

0.00

AC:

AN:

34920

South Asian (SAS)

AF:

0.0000530

AC:

AN:

37726

European-Finnish (FIN)

AF:

0.0000456

AC:

AN:

43892

Middle Eastern (MID)

AF:

0.000204

AC:

AN:

4894

European-Non Finnish (NFE)

AF:

0.000118

AC:

118

AN:

996766

Other (OTH)

AF:

0.000119

AC:

AN:

50318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000394

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000101

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000170

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 49

Uncertain:2

Jan 30, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 491 of the TECPR2 protein (p.Glu491Lys). This variant is present in population databases (rs751957510, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TECPR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 240923). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1471G>A (p.E491K) alteration is located in exon 9 (coding exon 8) of the TECPR2 gene. This alteration results from a G to A substitution at nucleotide position 1471, causing the glutamic acid (E) at amino acid position 491 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia

Uncertain:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TECPR2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.011

T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

4.9

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.052

T;T

Polyphen

1.0

D;.

Vest4

0.44

MVP

0.12

MPC

0.92

ClinPred

0.22

GERP RS

4.9

Varity_R

0.13

gMVP

0.29

Mutation Taster

=91/9

polymorphism

(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