Genetic Variant NM_152386.4:c.311C>A (chr2-222474659-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_152386.4(SGPP2):c.311C>A(p.Thr104Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,542 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T104M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SGPP2
NM_152386.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.09

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.878

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152386.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGPP2	NM_152386.4	MANE Select	c.311C>A	p.Thr104Lys	missense	Exon 2 of 5	NP_689599.2
SGPP2	NM_001320833.2		c.-74C>A		5_prime_UTR	Exon 3 of 6	NP_001307762.1	Q8IWX5-2
SGPP2	NM_001320834.2		c.-74C>A		5_prime_UTR	Exon 2 of 5	NP_001307763.1	Q8IWX5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGPP2	ENST00000321276.8	TSL:1 MANE Select	c.311C>A	p.Thr104Lys	missense	Exon 2 of 5	ENSP00000315137.7	Q8IWX5-1
SGPP2	ENST00000964572.1		c.311C>A	p.Thr104Lys	missense	Exon 2 of 5	ENSP00000634631.1
SGPP2	ENST00000852416.1		c.311C>A	p.Thr104Lys	missense	Exon 2 of 4	ENSP00000522475.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727112

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111748

Other (OTH)

AF:

0.00

AC:

AN:

60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.096

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.6

PhyloP100

6.1

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.61

Sift

Benign

0.075

Sift4G

Uncertain

0.048

Polyphen

0.88

Vest4

0.89

MutPred

0.59

Gain of ubiquitination at T104 (P = 0.023)

MVP

0.98

MPC

0.42

ClinPred

0.99

GERP RS

5.4

Varity_R

0.47

gMVP

0.85

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over