rs1018872661

Variant names:

• chr14-102434309-C-A
• rs1018872661
• NM_014844.5:c.1492C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014844.5(TECPR2):​c.1492C>A​(p.Gln498Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,292,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: TECPR2 NM_014844.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.86
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07631314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECPR2	NM_014844.5	c.1492C>A	p.Gln498Lys	missense_variant	Exon 9 of 20	ENST00000359520.12	NP_055659.2
TECPR2	NM_001172631.3	c.1492C>A	p.Gln498Lys	missense_variant	Exon 9 of 17		NP_001166102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECPR2	ENST00000359520.12	c.1492C>A	p.Gln498Lys	missense_variant	Exon 9 of 20	1	NM_014844.5	ENSP00000352510.7
TECPR2	ENST00000558678.1	c.1492C>A	p.Gln498Lys	missense_variant	Exon 9 of 17	1		ENSP00000453671.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000310 AC: 4 AN: 1292212 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 626080

African (AFR) AF: 0.00 AC: 0 AN: 29308

American (AMR) AF: 0.0000392 AC: 1 AN: 25498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18380

East Asian (EAS) AF: 0.00 AC: 0 AN: 37212

South Asian (SAS) AF: 0.00 AC: 0 AN: 50432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5094

European-Non Finnish (NFE) AF: 0.00000292 AC: 3 AN: 1026570

Other (OTH) AF: 0.00 AC: 0 AN: 53068

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 49 Uncertain:2

May 31, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 498 of the TECPR2 protein (p.Gln498Lys). This variant is not present in population databases (gnomAD no frequency). 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: 473088). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0029	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		1.9
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.030
Sift	Benign	0.15	T;T
Sift4G	Benign	0.75	T;T
Polyphen		0.16	B;.
Vest4		0.15
MutPred		0.23		Gain of ubiquitination at Q498 (P = 0.0011);Gain of ubiquitination at Q498 (P = 0.0011);
MVP		0.068
MPC		0.40
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.098
gMVP		0.27
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1018872661; hg19: chr14-102900646;