rs2273906

Variant names:

• chr14-102432026-C-T
• rs2273906
• NM_014844.5:c.1315C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014844.5(TECPR2):​c.1315C>T​(p.Pro439Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,612,818 control chromosomes in the GnomAD database, including 1,112 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P439L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.042 (157 hom., cov: 32)
  • Exomes 𝑓: 0.034 (955 hom.)
• Consequence: TECPR2 NM_014844.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.911
• Publications: 11 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022470057).
• BP6: Variant 14-102432026-C-T is Benign according to our data. Variant chr14-102432026-C-T is described in ClinVar as Benign. ClinVar VariationId is 380927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

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.1315C>T	p.Pro439Ser	missense	Exon 8 of 20	NP_055659.2	O15040-1
	TECPR2	NM_001172631.3		c.1315C>T	p.Pro439Ser	missense	Exon 8 of 17	NP_001166102.1	O15040-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECPR2	ENST00000359520.12	TSL:1 MANE Select	c.1315C>T	p.Pro439Ser	missense	Exon 8 of 20	ENSP00000352510.7	O15040-1
	TECPR2	ENST00000558678.1	TSL:1	c.1315C>T	p.Pro439Ser	missense	Exon 8 of 17	ENSP00000453671.1	O15040-2
	TECPR2	ENST00000856897.1		c.1315C>T	p.Pro439Ser	missense	Exon 8 of 20	ENSP00000526956.1

Frequencies

GnomAD3 genomes AF: 0.0417 AC: 6344 AN: 152192 Hom.: 157 Cov.: 32

Gnomad AFR AF: 0.0571

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.0343

Gnomad SAS AF: 0.0424

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0313

Gnomad OTH AF: 0.0521

GnomAD2 exomes AF: 0.0390 AC: 9512 AN: 244072 AF XY: 0.0378

Gnomad AFR exome AF: 0.0584

Gnomad AMR exome AF: 0.0627

Gnomad ASJ exome AF: 0.0488

Gnomad EAS exome AF: 0.0288

Gnomad FIN exome AF: 0.0375

Gnomad NFE exome AF: 0.0303

Gnomad OTH exome AF: 0.0402

GnomAD4 exome AF: 0.0336 AC: 49130 AN: 1460508 Hom.: 955 Cov.: 31 AF XY: 0.0334 AC XY: 24277 AN XY: 726556

African (AFR) AF: 0.0545 AC: 1826 AN: 33476

American (AMR) AF: 0.0604 AC: 2699 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 1227 AN: 26128

East Asian (EAS) AF: 0.0401 AC: 1593 AN: 39696

South Asian (SAS) AF: 0.0380 AC: 3279 AN: 86226

European-Finnish (FIN) AF: 0.0392 AC: 2051 AN: 52316

Middle Eastern (MID) AF: 0.0530 AC: 305 AN: 5758

European-Non Finnish (NFE) AF: 0.0306 AC: 34004 AN: 1111862

Other (OTH) AF: 0.0355 AC: 2146 AN: 60370

GnomAD4 genome AF: 0.0417 AC: 6350 AN: 152310 Hom.: 157 Cov.: 32 AF XY: 0.0416 AC XY: 3099 AN XY: 74474

African (AFR) AF: 0.0571 AC: 2372 AN: 41560

American (AMR) AF: 0.0454 AC: 694 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 158 AN: 3472

East Asian (EAS) AF: 0.0342 AC: 177 AN: 5178

South Asian (SAS) AF: 0.0425 AC: 205 AN: 4826

European-Finnish (FIN) AF: 0.0406 AC: 431 AN: 10620

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0313 AC: 2130 AN: 68034

Other (OTH) AF: 0.0525 AC: 111 AN: 2114

Alfa AF: 0.0345 Hom.: 277

Bravo AF: 0.0432

TwinsUK AF: 0.0297 AC: 110

ALSPAC AF: 0.0301 AC: 116

ESP6500AA AF: 0.0491 AC: 203

ESP6500EA AF: 0.0269 AC: 221

ExAC AF: 0.0372 AC: 4479

Asia WGS AF: 0.0480 AC: 165 AN: 3478

EpiCase AF: 0.0334

EpiControl AF: 0.0306

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 49 (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.91
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.086
Sift	Benign	0.41	T
Sift4G	Benign	0.26	T
Polyphen		0.036	B
Vest4		0.020
MPC		0.31
ClinPred		0.023	T
GERP RS		4.5
Varity_R		0.038
gMVP		0.26
Mutation Taster		=97/3	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: rs2273906; hg19: chr14-102898363; COSMIC: COSV107463668; COSMIC: COSV107463668;