chr14-102445813-C-A

Variant names:

• chr14-102445813-C-A
• rs62000389
• NM_014844.5:c.2941C>A

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.2941C>A​(p.Gln981Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,613,582 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 31)
  • Exomes 𝑓: 0.020 (337 hom.)
• Consequence: TECPR2 NM_014844.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.71
• Publications: 12 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=0.006488502).
• BP6: Variant 14-102445813-C-A is Benign according to our data. Variant chr14-102445813-C-A is described in ClinVar as Benign. ClinVar VariationId is 240924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2159/152076) while in subpopulation NFE AF = 0.0211 (1433/68000). AF 95% confidence interval is 0.0202. There are 24 homozygotes in GnomAd4. There are 1027 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECPR2	NM_014844.5	MANE Select	c.2941C>A	p.Gln981Lys	missense	Exon 13 of 20	NP_055659.2	O15040-1
	TECPR2	NM_001172631.3		c.2941C>A	p.Gln981Lys	missense	Exon 13 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.2941C>A	p.Gln981Lys	missense	Exon 13 of 20	ENSP00000352510.7	O15040-1
	TECPR2	ENST00000558678.1	TSL:1	c.2941C>A	p.Gln981Lys	missense	Exon 13 of 17	ENSP00000453671.1	O15040-2
	TECPR2	ENST00000856897.1		c.2941C>A	p.Gln981Lys	missense	Exon 13 of 20	ENSP00000526956.1

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2158 AN: 151958 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.00435

Gnomad AMI AF: 0.0795

Gnomad AMR AF: 0.00729

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0185

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0172 AC: 4327 AN: 251142 AF XY: 0.0184

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.00612

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0193

GnomAD4 exome AF: 0.0199 AC: 29031 AN: 1461506 Hom.: 337 Cov.: 31 AF XY: 0.0200 AC XY: 14566 AN XY: 727064

African (AFR) AF: 0.00523 AC: 175 AN: 33468

American (AMR) AF: 0.00687 AC: 307 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 768 AN: 26120

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39686

South Asian (SAS) AF: 0.0217 AC: 1868 AN: 86234

European-Finnish (FIN) AF: 0.0135 AC: 721 AN: 53410

Middle Eastern (MID) AF: 0.0297 AC: 171 AN: 5760

European-Non Finnish (NFE) AF: 0.0215 AC: 23953 AN: 1111768

Other (OTH) AF: 0.0176 AC: 1060 AN: 60374

GnomAD4 genome AF: 0.0142 AC: 2159 AN: 152076 Hom.: 24 Cov.: 31 AF XY: 0.0138 AC XY: 1027 AN XY: 74336

African (AFR) AF: 0.00439 AC: 182 AN: 41476

American (AMR) AF: 0.00728 AC: 111 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.0183 AC: 88 AN: 4812

European-Finnish (FIN) AF: 0.0142 AC: 150 AN: 10580

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1433 AN: 68000

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.0196 Hom.: 131

Bravo AF: 0.0136

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0221 AC: 190

ExAC AF: 0.0183 AC: 2219

Asia WGS AF: 0.00982 AC: 35 AN: 3478

EpiCase AF: 0.0199

EpiControl AF: 0.0221

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hereditary spastic paraplegia 49 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.24
Sift	Benign	0.047	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.21
MPC		0.57
ClinPred		0.036	T
GERP RS		5.3
Varity_R		0.36
gMVP		0.78
Mutation Taster		=89/11	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: rs62000389; hg19: chr14-102912150; COSMIC: COSV63970627; COSMIC: COSV63970627;