5-138444447-T-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001271803.2(REEP2):​c.215T>G​(p.Phe72Cys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F72Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: REEP2 NM_001271803.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REEP2	NM_001271803.2	c.215T>G	p.Phe72Cys	missense_variant	Exon 4 of 8	ENST00000378339.7	NP_001258732.1
REEP2	NM_016606.4	c.215T>G	p.Phe72Cys	missense_variant	Exon 4 of 8		NP_057690.2
REEP2	NR_073448.2	n.442T>G		non_coding_transcript_exon_variant	Exon 4 of 8
REEP2	NR_073449.2	n.442T>G		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REEP2	ENST00000378339.7	c.215T>G	p.Phe72Cys	missense_variant	Exon 4 of 8	1	NM_001271803.2	ENSP00000367590.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;D;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	4.1	H;H;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.0	D;D;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.97	.;D;.;.
Vest4		0.88
MutPred		0.78		Gain of ubiquitination at K69 (P = 0.1047);Gain of ubiquitination at K69 (P = 0.1047);.;.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		0.97
Mutation Taster		=37/63	disease causing

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;