5-138441404-G-C

Position:

• chr5-138441404-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001271803.2(REEP2):​c.125G>C​(p.Trp42Ser) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: REEP2 NM_001271803.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REEP2	NM_001271803.2	c.125G>C	p.Trp42Ser	missense_variant	3/8	ENST00000378339.7	NP_001258732.1
REEP2	NM_016606.4	c.125G>C	p.Trp42Ser	missense_variant	3/8		NP_057690.2
REEP2	NR_073448.2	n.352G>C		non_coding_transcript_exon_variant	3/8
REEP2	NR_073449.2	n.352G>C		non_coding_transcript_exon_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REEP2	ENST00000378339.7	c.125G>C	p.Trp42Ser	missense_variant	3/8	1	NM_001271803.2	ENSP00000367590.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 72 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen

Jul 12, 2021

The variant is absent from databases and has not been reported in the literature. We have classified it as a "Variant of uncertain significance". -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;D;.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-14	D;D;D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.97	.;D;.;.
Vest4		0.93
MutPred		0.84		Loss of MoRF binding (P = 0.0518);Loss of MoRF binding (P = 0.0518);.;.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.95
gMVP		0.99

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-137777093;