rs118141823

Variant names:

• chr14-102434619-C-T
• rs118141823
• NM_014844.5:c.1802C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014844.5(TECPR2):​c.1802C>T​(p.Pro601Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,583,794 control chromosomes in the GnomAD database, including 353 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P601P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (29 hom., cov: 32)
  • Exomes 𝑓: 0.020 (324 hom.)
• Consequence: TECPR2 NM_014844.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0500
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002579838).
• BP6: Variant 14-102434619-C-T is Benign according to our data. Variant chr14-102434619-C-T is described in ClinVar as Benign. ClinVar VariationId is 220729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0165 (2506/152272) while in subpopulation AMR AF = 0.0281 (429/15294). AF 95% confidence interval is 0.0259. There are 29 homozygotes in GnomAd4. There are 1195 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECPR2	NM_014844.5	MANE Select	c.1802C>T	p.Pro601Leu	missense	Exon 9 of 20	NP_055659.2
	TECPR2	NM_001172631.3		c.1802C>T	p.Pro601Leu	missense	Exon 9 of 17	NP_001166102.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECPR2	ENST00000359520.12	TSL:1 MANE Select	c.1802C>T	p.Pro601Leu	missense	Exon 9 of 20	ENSP00000352510.7
	TECPR2	ENST00000558678.1	TSL:1	c.1802C>T	p.Pro601Leu	missense	Exon 9 of 17	ENSP00000453671.1
	TECPR2	ENST00000856897.1		c.1802C>T	p.Pro601Leu	missense	Exon 9 of 20	ENSP00000526956.1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2510 AN: 152154 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0281

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.0165 AC: 3847 AN: 233650 AF XY: 0.0165

Gnomad AFR exome AF: 0.00453

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0215

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0197 AC: 28271 AN: 1431522 Hom.: 324 Cov.: 30 AF XY: 0.0194 AC XY: 13689 AN XY: 707384

African (AFR) AF: 0.00360 AC: 119 AN: 33052

American (AMR) AF: 0.0208 AC: 900 AN: 43320

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 780 AN: 24094

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39294

South Asian (SAS) AF: 0.00834 AC: 683 AN: 81868

European-Finnish (FIN) AF: 0.0142 AC: 741 AN: 52308

Middle Eastern (MID) AF: 0.00407 AC: 23 AN: 5650

European-Non Finnish (NFE) AF: 0.0218 AC: 23868 AN: 1092864

Other (OTH) AF: 0.0196 AC: 1156 AN: 59072

GnomAD4 genome AF: 0.0165 AC: 2506 AN: 152272 Hom.: 29 Cov.: 32 AF XY: 0.0161 AC XY: 1195 AN XY: 74442

African (AFR) AF: 0.00392 AC: 163 AN: 41554

American (AMR) AF: 0.0281 AC: 429 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 115 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4826

European-Finnish (FIN) AF: 0.0109 AC: 116 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0227 AC: 1545 AN: 68022

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0199 Hom.: 138

Bravo AF: 0.0174

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0229 AC: 197

ExAC AF: 0.0165 AC: 2002

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 49 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.5
DANN	Benign	0.96
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.050
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.046
Sift	Uncertain	0.021	D
Sift4G	Benign	0.49	T
Polyphen		0.0040	B
Vest4		0.022
MPC		0.31
ClinPred		0.0062	T
GERP RS		-0.26
Varity_R		0.032
gMVP		0.20
Mutation Taster		=98/2	polymorphism (auto)

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: rs118141823; hg19: chr14-102900956;