rs1064792986

Variant names:

• chr2-86232666-GGCTGGCCGTGTTTGCC-G
• rs1064792986
• NM_001371279.1:c.538_553delGGCAAACACGGCCAGC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001371279.1(REEP1):​c.538_553delGGCAAACACGGCCAGC​(p.Gly180LeufsTer32) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G180G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: REEP1 NM_001371279.1 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.31
• Publications: 0 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-86232666-GGCTGGCCGTGTTTGCC-G is Pathogenic according to our data. Variant chr2-86232666-GGCTGGCCGTGTTTGCC-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 411806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.538_553delGGCAAACACGGCCAGC	p.Gly180LeufsTer32	frameshift	Exon 6 of 9	NP_001358208.1	A0A1C7CYY3
	REEP1	NM_001410855.1		c.538_553delGGCAAACACGGCCAGC	p.Gly180LeufsTer20	frameshift	Exon 6 of 8	NP_001397784.1	A0A2R8Y6K6
	REEP1	NM_001410856.1		c.538_553delGGCAAACACGGCCAGC	p.Gly180LeufsTer50	frameshift	Exon 6 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.538_553delGGCAAACACGGCCAGC	p.Gly180LeufsTer32	frameshift	Exon 6 of 9	ENSP00000438346.3	A0A1C7CYY3
	REEP1	ENST00000165698.9	TSL:1	c.538_553delGGCAAACACGGCCAGC	p.Gly180LeufsTer38	frameshift	Exon 6 of 7	ENSP00000165698.5	Q9H902-1
	REEP1	ENST00000908467.1		c.688_703delGGCAAACACGGCCAGC	p.Gly230LeufsTer20	frameshift	Exon 7 of 9	ENSP00000578526.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary spastic paraplegia 31 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1064792986; hg19: chr2-86459789;