14-102414778-C-T

Position:

chr14-102414778-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_014844.5(TECPR2):c.623C>T(p.Thr208Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000205 in 1,614,142 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T208A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

TECPR2
NM_014844.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 5.68

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009041369).

BP6

Variant 14-102414778-C-T is Benign according to our data. Variant chr14-102414778-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473092.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00132 (201/152330) while in subpopulation AFR AF= 0.00472 (196/41568). AF 95% confidence interval is 0.00418. There are 0 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECPR2	NM_014844.5 linkuse as main transcript	c.623C>T	p.Thr208Ile	missense_variant	5/20	ENST00000359520.12
TECPR2	NM_001172631.3 linkuse as main transcript	c.623C>T	p.Thr208Ile	missense_variant	5/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECPR2	ENST00000359520.12 linkuse as main transcript	c.623C>T	p.Thr208Ile	missense_variant	5/20	1	NM_014844.5	P1	O15040-1
TECPR2	ENST00000558678.1 linkuse as main transcript	c.623C>T	p.Thr208Ile	missense_variant	5/17	1			O15040-2
TECPR2	ENST00000561228.1 linkuse as main transcript	n.751C>T		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes

AF:

0.00132

AC:

201

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00473

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000326

AC:

AN:

251370

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00480

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000889

AC:

130

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00344

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.00132

AC:

201

AN:

152330

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00472

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000251

Hom.:

Bravo

AF:

0.00131

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000486

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 49

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 15, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

TECPR2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.0090

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

0.90

N;N

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.13

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.94

P;.

Vest4

0.37

MVP

0.068

MPC

0.87

ClinPred

0.099

GERP RS

4.9

Varity_R

0.36

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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