rs2276625

Variant names:

• chr2-86254712-C-T
• rs2276625
• NM_001371279.1:c.285G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 29 publications found

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]

REEP1 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 31

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• neuronopathy, distal hereditary motor, type 5B

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• neuronopathy, distal hereditary motor, type 5A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spinal muscular atrophy, distal, autosomal recessive, 6

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 130108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371279.1. 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
	REEP1	NM_001371279.1	MANE Select	c.285G>A	p.Thr95Thr	synonymous	Exon 4 of 9	NP_001358208.1	A0A1C7CYY3
	REEP1	NM_001410855.1		c.285G>A	p.Thr95Thr	synonymous	Exon 4 of 8	NP_001397784.1	A0A2R8Y6K6
	REEP1	NM_001410856.1		c.285G>A	p.Thr95Thr	synonymous	Exon 4 of 8	NP_001397785.1	A0A8I5QKJ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP1	ENST00000538924.7	TSL:5 MANE Select	c.285G>A	p.Thr95Thr	synonymous	Exon 4 of 9	ENSP00000438346.3	A0A1C7CYY3
	REEP1	ENST00000165698.9	TSL:1	c.285G>A	p.Thr95Thr	synonymous	Exon 4 of 7	ENSP00000165698.5	Q9H902-1
	REEP1	ENST00000908467.1		c.285G>A	p.Thr95Thr	synonymous	Exon 4 of 9	ENSP00000578526.1

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

GnomAD2 exomes AF: 0.475 AC: 119360 AN: 251322 AF XY: 0.474

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 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

African (AFR) AF: 0.211 AC: 7041 AN: 33428

American (AMR) AF: 0.607 AC: 27123 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 11735 AN: 26096

East Asian (EAS) AF: 0.593 AC: 23514 AN: 39676

South Asian (SAS) AF: 0.454 AC: 39096 AN: 86178

European-Finnish (FIN) AF: 0.496 AC: 26478 AN: 53364

Middle Eastern (MID) AF: 0.439 AC: 2532 AN: 5764

European-Non Finnish (NFE) AF: 0.443 AC: 491045 AN: 1108804

Other (OTH) AF: 0.440 AC: 26533 AN: 60310

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

African (AFR) AF: 0.222 AC: 9223 AN: 41502

American (AMR) AF: 0.503 AC: 7689 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1580 AN: 3470

East Asian (EAS) AF: 0.589 AC: 3046 AN: 5168

South Asian (SAS) AF: 0.454 AC: 2188 AN: 4824

European-Finnish (FIN) AF: 0.506 AC: 5351 AN: 10578

Middle Eastern (MID) AF: 0.428 AC: 125 AN: 292

European-Non Finnish (NFE) AF: 0.445 AC: 30234 AN: 67972

Other (OTH) AF: 0.427 AC: 901 AN: 2108

Alfa AF: 0.435 Hom.: 24431

Bravo AF: 0.395

Asia WGS AF: 0.496 AC: 1724 AN: 3478

EpiCase AF: 0.443

EpiControl AF: 0.451

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Hereditary spastic paraplegia 31 (4)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Neuronopathy, distal hereditary motor, type 5B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.0
DANN	Benign	0.39
PhyloP100		-3.1
Mutation Taster		=100/0	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: rs2276625; hg19: chr2-86481835; COSMIC: COSV51256772;