rs200469835
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_014844.5(TECPR2):āc.541A>Gā(p.Ser181Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,230 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 Uncertain significance (ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.000012 ( 0 hom. )
Consequence
TECPR2
NM_014844.5 missense
NM_014844.5 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 8.82
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.062091082).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TECPR2 | NM_014844.5 | c.541A>G | p.Ser181Gly | missense_variant | 5/20 | ENST00000359520.12 | NP_055659.2 | |
TECPR2 | NM_001172631.3 | c.541A>G | p.Ser181Gly | missense_variant | 5/17 | NP_001166102.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TECPR2 | ENST00000359520.12 | c.541A>G | p.Ser181Gly | missense_variant | 5/20 | 1 | NM_014844.5 | ENSP00000352510 | P1 | |
TECPR2 | ENST00000558678.1 | c.541A>G | p.Ser181Gly | missense_variant | 5/17 | 1 | ENSP00000453671 | |||
TECPR2 | ENST00000561228.1 | n.669A>G | non_coding_transcript_exon_variant | 5/6 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251480Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135912
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461890Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 727248
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152340Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74508
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 49 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 27, 2021 | This sequence change replaces serine with glycine at codon 181 of the TECPR2 protein (p.Ser181Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs200469835, ExAC 0.06%). This variant has not been reported in the literature in individuals affected with TECPR2-related conditions. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Uncertain
D;D
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at