14-102434309-C-A

Position:

• chr14-102434309-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 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

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 Uncertain_significance. Variant got 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/exons	MANE	UniProt
TECPR2	NM_014844.5	c.1492C>A	p.Gln498Lys	missense_variant	9/20	ENST00000359520.12
TECPR2	NM_001172631.3	c.1492C>A	p.Gln498Lys	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECPR2	ENST00000359520.12	c.1492C>A	p.Gln498Lys	missense_variant	9/20	1	NM_014844.5	P1
TECPR2	ENST00000558678.1	c.1492C>A	p.Gln498Lys	missense_variant	9/17	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000392

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000292

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2022	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 31, 2021	- -

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
MutationTaster	Benign	1.0	N;N
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

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: rs1018872661; hg19: chr14-102900646;