chr14-102434617-G-A

Variant names:

• chr14-102434617-G-A
• rs749351336
• NM_014844.5:c.1800G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_014844.5(TECPR2):​c.1800G>A​(p.Glu600Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,430,552 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TECPR2 NM_014844.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.122
• 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-102434617-G-A is Benign according to our data. Variant chr14-102434617-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 415303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.122 with no splicing effect.

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.1800G>A	p.Glu600Glu	synonymous	Exon 9 of 20	NP_055659.2	O15040-1
	TECPR2	NM_001172631.3		c.1800G>A	p.Glu600Glu	synonymous	Exon 9 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.1800G>A	p.Glu600Glu	synonymous	Exon 9 of 20	ENSP00000352510.7	O15040-1
	TECPR2	ENST00000558678.1	TSL:1	c.1800G>A	p.Glu600Glu	synonymous	Exon 9 of 17	ENSP00000453671.1	O15040-2
	TECPR2	ENST00000856897.1		c.1800G>A	p.Glu600Glu	synonymous	Exon 9 of 20	ENSP00000526956.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000860 AC: 2 AN: 232578 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1430552 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 706742

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33040

American (AMR) AF: 0.00 AC: 0 AN: 43328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24044

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

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092286

Other (OTH) AF: 0.00 AC: 0 AN: 59034

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia 49 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.1
DANN	Benign	0.47
PhyloP100		-0.12

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: rs749351336; hg19: chr14-102900954;