chr2-86282217-C-T

Variant names:

• chr2-86282217-C-T
• rs1266102026
• NM_001371279.1:c.58G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001371279.1(REEP1):​c.58G>A​(p.Ala20Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A20E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: REEP1 NM_001371279.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.31
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001371279.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-86282216-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP1	NM_001371279.1	MANE Select	c.58G>A	p.Ala20Thr	missense	Exon 2 of 9	NP_001358208.1
	REEP1	NM_001410855.1		c.58G>A	p.Ala20Thr	missense	Exon 2 of 8	NP_001397784.1
	REEP1	NM_001410856.1		c.58G>A	p.Ala20Thr	missense	Exon 2 of 8	NP_001397785.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP1	ENST00000538924.7	TSL:5 MANE Select	c.58G>A	p.Ala20Thr	missense	Exon 2 of 9	ENSP00000438346.3
	REEP1	ENST00000165698.9	TSL:1	c.58G>A	p.Ala20Thr	missense	Exon 2 of 7	ENSP00000165698.5
	REEP1	ENST00000642243.1		c.16G>A	p.Ala6Thr	missense	Exon 1 of 9	ENSP00000494960.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251408 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457404 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725388

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107990

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Jun 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Dec 20, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18321925, 20718791, 16826527)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.68		Gain of methylation at K25 (P = 0.0985)
MVP		0.90
MPC		1.7
ClinPred		0.99	D
GERP RS		4.3
PromoterAI		-0.0021	Neutral
Varity_R		0.62
gMVP		0.80
Mutation Taster		=199/101	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1266102026; hg19: chr2-86509340;