rs45467297

chr14-102434867-C-Gchr14-102434867-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.443

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 380957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102434867-C-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
TECPR2	NM_014844.5	c.2050C>G	p.Leu684Val	missense_variant	9/20	ENST00000359520.12
TECPR2	NM_001172631.3	c.2050C>G	p.Leu684Val	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECPR2	ENST00000359520.12	c.2050C>G	p.Leu684Val	missense_variant	9/20	1	NM_014844.5	P1
TECPR2	ENST00000558678.1	c.2050C>G	p.Leu684Val	missense_variant	9/17	1
TECPR2	ENST00000560060.5	n.29C>G		non_coding_transcript_exon_variant	1/5	4

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5078 AN: 152238 Hom.: 137 Cov.: 32

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

GnomAD3 exomes AF: 0.0438 AC: 10985 AN: 250750 Hom.: 379 AF XY: 0.0430 AC XY: 5835 AN XY: 135608

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 SAS exome AF: 0.0513

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.: 33 AF XY: 0.0453 AC XY: 32918 AN XY: 726962

Gnomad4 AFR exome AF: 0.00759

Gnomad4 AMR exome AF: 0.0871

Gnomad4 ASJ exome AF: 0.0262

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0505

Gnomad4 FIN exome AF: 0.0310

Gnomad4 NFE exome AF: 0.0477

Gnomad4 OTH exome AF: 0.0409

GnomAD4 genome AF: 0.0333 AC: 5075 AN: 152356 Hom.: 136 Cov.: 32 AF XY: 0.0331 AC XY: 2466 AN XY: 74498

Gnomad4 AFR AF: 0.00791

Gnomad4 AMR AF: 0.0640

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0516

Gnomad4 FIN AF: 0.0293

Gnomad4 NFE AF: 0.0433

Gnomad4 OTH AF: 0.0345

Alfa AF: 0.0384 Hom.: 47

Bravo AF: 0.0347

TwinsUK AF: 0.0504 AC: 187

ALSPAC AF: 0.0400 AC: 154

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.0413 AC: 355

ExAC AF: 0.0423 AC: 5142

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.0408

EpiControl AF: 0.0396

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 49 Benign:4

Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 27, 2017	- -
Benign, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Jul 11, 2020	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). -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	May 17, 2017	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2016	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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	2.0
Dann	Benign	0.82
DEOGEN2	Benign	0.0057	T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
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	T
GERP RS		1.7
Varity_R		0.022
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs45467297; hg19: chr14-102901204;