chr14-102445813-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014844.5(TECPR2):c.2941C>A(p.Gln981Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,613,582 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 31)

Exomes 𝑓: 0.020 ( 337 hom. )

Consequence

TECPR2
NM_014844.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.71

Publications

12 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=0.006488502).

BP6

Variant 14-102445813-C-A is Benign according to our data. Variant chr14-102445813-C-A is described in ClinVar as Benign. ClinVar VariationId is 240924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2159/152076) while in subpopulation NFE AF = 0.0211 (1433/68000). AF 95% confidence interval is 0.0202. There are 24 homozygotes in GnomAd4. There are 1027 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECPR2	NM_014844.5 link	c.2941C>A	p.Gln981Lys	missense_variant	Exon 13 of 20	ENST00000359520.12	NP_055659.2	O15040-1
TECPR2	NM_001172631.3 link	c.2941C>A	p.Gln981Lys	missense_variant	Exon 13 of 17		NP_001166102.1	O15040-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TECPR2	ENST00000359520.12 link	c.2941C>A	p.Gln981Lys	missense_variant	Exon 13 of 20	1	NM_014844.5	ENSP00000352510.7	O15040-1
TECPR2	ENST00000558678.1 link	c.2941C>A	p.Gln981Lys	missense_variant	Exon 13 of 17	1		ENSP00000453671.1	O15040-2
TECPR2	ENST00000557786.1 link	n.550C>A		non_coding_transcript_exon_variant	Exon 4 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2158

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00435

Gnomad AMI

AF:

0.0795

Gnomad AMR

AF:

0.00729

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0185

Gnomad FIN

AF:

0.0142

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0172

AC:

4327

AN:

251142

AF XY:

0.0184

show subpopulations

Gnomad AFR exome

AF:

0.00449

Gnomad AMR exome

AF:

0.00612

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0142

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0193

GnomAD4 exome

AF:

0.0199

AC:

29031

AN:

1461506

Hom.:

337

Cov.:

AF XY:

0.0200

AC XY:

14566

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.00523

AC:

175

AN:

33468

American (AMR)

AF:

0.00687

AC:

307

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

768

AN:

26120

East Asian (EAS)

AF:

0.000202

AC:

AN:

39686

South Asian (SAS)

AF:

0.0217

AC:

1868

AN:

86234

European-Finnish (FIN)

AF:

0.0135

AC:

721

AN:

53410

Middle Eastern (MID)

AF:

0.0297

AC:

171

AN:

5760

European-Non Finnish (NFE)

AF:

0.0215

AC:

23953

AN:

1111768

Other (OTH)

AF:

0.0176

AC:

1060

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1498

2995

4493

5990

7488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

894

1788

2682

3576

4470

<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:

0.0142

AC:

2159

AN:

152076

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1027

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00439

AC:

182

AN:

41476

American (AMR)

AF:

0.00728

AC:

111

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.0183

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0142

AC:

150

AN:

10580

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0211

AC:

1433

AN:

68000

Other (OTH)

AF:

0.0132

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

106

211

317

422

528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0196

Hom.:

131

Bravo

AF:

0.0136

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0221

AC:

190

ExAC

AF:

0.0183

AC:

2219

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.0199

EpiControl

AF:

0.0221

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 01, 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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 49

Benign:2

Nov 26, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Nov 23, 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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

T;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0065

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

2.9

M;M

PhyloP100

7.7

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.24

Sift

Benign

0.047

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

1.0

D;.

Vest4

0.21

MPC

0.57

ClinPred

0.036

GERP RS

5.3

Varity_R

0.36

gMVP

0.78

Mutation Taster

=89/11

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