chr5-138444447-T-A

Variant names:

• chr5-138444447-T-A
• rs483352925
• NM_001271803.2:c.215T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001271803.2(REEP2):​c.215T>A​(p.Phe72Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: REEP2 NM_001271803.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.98
• Publications: 5 publications found

Genes affected

REEP2 (HGNC:17975): (receptor accessory protein 2) This gene encodes a member of the receptor expression enhancing protein family. Studies of a related gene in mouse suggest that the encoded protein is found in the cell membrane and enhances the function of sweet taste receptors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

REEP2 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 72

  Inheritance: SD, AD, AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary spastic paraplegia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 5-138444447-T-A is Pathogenic according to our data. Variant chr5-138444447-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 97004.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271803.2. 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
	REEP2	NM_001271803.2	MANE Select	c.215T>A	p.Phe72Tyr	missense	Exon 4 of 8	NP_001258732.1	Q9BRK0-2
	REEP2	NM_016606.4		c.215T>A	p.Phe72Tyr	missense	Exon 4 of 8	NP_057690.2
	REEP2	NR_073448.2		n.442T>A		non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP2	ENST00000378339.7	TSL:1 MANE Select	c.215T>A	p.Phe72Tyr	missense	Exon 4 of 8	ENSP00000367590.2	Q9BRK0-2
	REEP2	ENST00000254901.9	TSL:1	c.215T>A	p.Phe72Tyr	missense	Exon 4 of 8	ENSP00000254901.5	Q9BRK0-1
	REEP2	ENST00000903314.1		c.215T>A	p.Phe72Tyr	missense	Exon 4 of 8	ENSP00000573373.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Spastic paraplegia 72b, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.75		Loss of stability (P = 0.0879)
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.83
gMVP		0.90
Mutation Taster		=14/86	disease causing (ClinVar)

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: rs483352925; hg19: chr5-137780136;