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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014844.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECPR2	NM_014844.5	MANE Select	c.1492C>A	p.Gln498Lys	missense	Exon 9 of 20	NP_055659.2
	TECPR2	NM_001172631.3		c.1492C>A	p.Gln498Lys	missense	Exon 9 of 17	NP_001166102.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECPR2	ENST00000359520.12	TSL:1 MANE Select	c.1492C>A	p.Gln498Lys	missense	Exon 9 of 20	ENSP00000352510.7
	TECPR2	ENST00000558678.1	TSL:1	c.1492C>A	p.Gln498Lys	missense	Exon 9 of 17	ENSP00000453671.1
	TECPR2	ENST00000856897.1		c.1492C>A	p.Gln498Lys	missense	Exon 9 of 20	ENSP00000526956.1

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary spastic paraplegia 49 (2)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.9
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.030
Sift	Benign	0.15	T
Sift4G	Benign	0.75	T
Polyphen		0.16	B
Vest4		0.15
MutPred		0.23		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;