Genetic Variant SPSB2:p.Leu171Val (chr12-6872391-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032641.4(SPSB2):c.511C>G(p.Leu171Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,216 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

SPSB2
NM_032641.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

Variant links:

Genes affected

SPSB2 (HGNC:29522): (splA/ryanodine receptor domain and SOCS box containing 2) This gene encodes a member of a subfamily of proteins containing a central SPRY (repeats in splA and RyR) domain and a C-terminal suppressor of cytokine signaling (SOCS) box. This protein plays a role in cell signaling. This gene is present in a gene-rich cluster on chromosome 12p13 in the vicinity of the CD4 antigen and triosephosphate isomerase genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

SPSB2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPSB2	NM_032641.4 link	c.511C>G	p.Leu171Val	missense_variant	Exon 2 of 3	ENST00000524270.6	NP_116030.1	Q99619-1
SPSB2	NM_001146316.2 link	c.511C>G	p.Leu171Val	missense_variant	Exon 2 of 3		NP_001139788.1	Q99619-1
SPSB2	NM_001319670.2 link	c.511C>G	p.Leu171Val	missense_variant	Exon 1 of 2		NP_001306599.1	Q99619-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPSB2	ENST00000524270.6 link	c.511C>G	p.Leu171Val	missense_variant	Exon 2 of 3	1	NM_032641.4	ENSP00000428338.1	Q99619-1
SPSB2	ENST00000523102.5 link	c.511C>G	p.Leu171Val	missense_variant	Exon 2 of 3	1		ENSP00000430872.1	Q99619-1
SPSB2	ENST00000519357.1 link	c.511C>G	p.Leu171Val	missense_variant	Exon 2 of 2	2		ENSP00000431037.1	Q99619-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.511C>G (p.L171V) alteration is located in exon 2 (coding exon 1) of the SPSB2 gene. This alteration results from a C to G substitution at nucleotide position 511, causing the leucine (L) at amino acid position 171 to be replaced by a valine (V). 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

0.32

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;D;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.64

LIST_S2

Pathogenic

1.0

.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.9

M;M;M

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.020

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.81

MutPred

0.62

Gain of catalytic residue at G176 (P = 3e-04);Gain of catalytic residue at G176 (P = 3e-04);Gain of catalytic residue at G176 (P = 3e-04);

MVP

0.67

MPC

0.85

ClinPred

0.99

GERP RS

2.1

Varity_R

0.86

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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