chr2-86254712-C-T

Position:

• chr2-86254712-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001371279.1(REEP1):​c.285G>A​(p.Thr95Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,610,440 control chromosomes in the GnomAD database, including 163,244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13073 hom., cov: 33)
  • Exomes 𝑓: 0.45 (150171 hom.)
• Consequence: REEP1 NM_001371279.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.15

Genes affected

REEP1 (HGNC:25786): (receptor accessory protein 1) This gene encodes a mitochondrial protein that functions to enhance the cell surface expression of odorant receptors. Mutations in this gene cause spastic paraplegia autosomal dominant type 31, a neurodegenerative disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-86254712-C-T is Benign according to our data. Variant chr2-86254712-C-T is described in ClinVar as [Benign]. Clinvar id is 130108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-86254712-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REEP1	NM_001371279.1	c.285G>A	p.Thr95Thr	synonymous_variant	4/9	ENST00000538924.7	NP_001358208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REEP1	ENST00000538924.7	c.285G>A	p.Thr95Thr	synonymous_variant	4/9	5	NM_001371279.1	ENSP00000438346.3

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60496 AN: 151990 Hom.: 13051 Cov.: 33

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.430

GnomAD3 exomes AF: 0.475 AC: 119360 AN: 251322 Hom.: 29674 AF XY: 0.474 AC XY: 64362 AN XY: 135836

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.619

Gnomad ASJ exome AF: 0.452

Gnomad EAS exome AF: 0.607

Gnomad SAS exome AF: 0.454

Gnomad FIN exome AF: 0.496

Gnomad NFE exome AF: 0.450

Gnomad OTH exome AF: 0.478

GnomAD4 exome AF: 0.449 AC: 655097 AN: 1458332 Hom.: 150171 Cov.: 34 AF XY: 0.449 AC XY: 325952 AN XY: 725598

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.607

Gnomad4 ASJ exome AF: 0.450

Gnomad4 EAS exome AF: 0.593

Gnomad4 SAS exome AF: 0.454

Gnomad4 FIN exome AF: 0.496

Gnomad4 NFE exome AF: 0.443

Gnomad4 OTH exome AF: 0.440

GnomAD4 genome AF: 0.398 AC: 60545 AN: 152108 Hom.: 13073 Cov.: 33 AF XY: 0.405 AC XY: 30105 AN XY: 74358

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.503

Gnomad4 ASJ AF: 0.455

Gnomad4 EAS AF: 0.589

Gnomad4 SAS AF: 0.454

Gnomad4 FIN AF: 0.506

Gnomad4 NFE AF: 0.445

Gnomad4 OTH AF: 0.427

Alfa AF: 0.440 Hom.: 20297

Bravo AF: 0.395

Asia WGS AF: 0.496 AC: 1724 AN: 3478

EpiCase AF: 0.443

EpiControl AF: 0.451

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary spastic paraplegia 31 Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Neuronopathy, distal hereditary motor, type 5B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.0
DANN	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs2276625; hg19: chr2-86481835; COSMIC: COSV51256772;