5-138439209-A-G

Variant names:

• chr5-138439209-A-G
• rs2127020121
• NM_001271803.2:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001271803.2(REEP2):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000163 in 1,227,510 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 (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: REEP2 NM_001271803.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13
• Publications: 0 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: AD, AR, SD 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 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 39 codons. Genomic position: 138441394. Lost 0.150 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.1A>G	p.Met1?	start_lost	Exon 1 of 8	NP_001258732.1	Q9BRK0-2
	REEP2	NM_016606.4		c.1A>G	p.Met1?	start_lost	Exon 1 of 8	NP_057690.2
	REEP2	NR_073448.2		n.153A>G		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP2	ENST00000378339.7	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 8	ENSP00000367590.2	Q9BRK0-2
	REEP2	ENST00000254901.9	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 8	ENSP00000254901.5	Q9BRK0-1
	REEP2	ENST00000903314.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 8	ENSP00000573373.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000163 AC: 2 AN: 1227510 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 600266

African (AFR) AF: 0.00 AC: 0 AN: 25250

American (AMR) AF: 0.00 AC: 0 AN: 19374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18004

East Asian (EAS) AF: 0.00 AC: 0 AN: 30940

South Asian (SAS) AF: 0.00 AC: 0 AN: 43060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4096

European-Non Finnish (NFE) AF: 0.00000200 AC: 2 AN: 998502

Other (OTH) AF: 0.00 AC: 0 AN: 49212

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 72 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.55	D
PhyloP100		6.1
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.87
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.59	P
Vest4		0.89
MutPred		0.98		Loss of disorder (P = 0.1031)
MVP		0.94
ClinPred		0.99	D
GERP RS		4.3
PromoterAI		-0.40	Neutral
Varity_R		0.60
gMVP		0.89
Mutation Taster		=5/195	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: rs2127020121; hg19: chr5-137774898;