Genetic Variant SGPP2:p.Arg44Trp (chr2-222424732-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152386.4(SGPP2):c.130C>T(p.Arg44Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000587 in 1,431,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

SGPP2
NM_152386.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.440

Variant links:

Genes affected

SGPP2 (HGNC:19953): (sphingosine-1-phosphate phosphatase 2) The protein encoded by this gene is a transmembrane protein that degrades the bioactive signaling molecule sphingosine 1-phosphate. The encoded protein is induced during inflammatory responses and has been shown to be downregulated by the microRNA-31 tumor suppressor. Alternative splice variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2016]

SGPP2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23421979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGPP2	NM_152386.4 link	c.130C>T	p.Arg44Trp	missense_variant	Exon 1 of 5	ENST00000321276.8	NP_689599.2	Q8IWX5-1
SGPP2	NM_001320833.2 link	c.-398C>T		5_prime_UTR_variant	Exon 1 of 6		NP_001307762.1	Q8IWX5-2
SGPP2	NM_001320834.2 link	c.-166+654C>T		intron_variant	Intron 1 of 4		NP_001307763.1	Q8IWX5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGPP2	ENST00000321276.8 link	c.130C>T	p.Arg44Trp	missense_variant	Exon 1 of 5	1	NM_152386.4	ENSP00000315137.7		Q8IWX5-1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000312

AC:

AN:

64148

Hom.:

AF XY:

0.0000536

AC XY:

AN XY:

37316

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000854

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000602

AC:

AN:

1279318

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

627716

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000663

Gnomad4 OTH exome

AF:

0.000171

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.130C>T (p.R44W) alteration is located in exon 1 (coding exon 1) of the SGPP2 gene. This alteration results from a C to T substitution at nucleotide position 130, causing the arginine (R) at amino acid position 44 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.9

REVEL

Benign

0.064

Sift

Uncertain

0.016

Sift4G

Uncertain

0.0060

Polyphen

0.99

Vest4

0.18

MutPred

0.37

Loss of methylation at R44 (P = 0.0281);

MVP

0.21

MPC

0.17

ClinPred

0.15

GERP RS

3.0

Varity_R

0.065

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over