chr12-6872457-C-T

Variant names:

Variant summary

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

The NM_032641.4(SPSB2):c.445G>A(p.Ala149Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SPSB2
NM_032641.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.784

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:

Genome browser will be placed here

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=0.07884982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPSB2	NM_032641.4 link	c.445G>A	p.Ala149Thr	missense_variant	Exon 2 of 3	ENST00000524270.6	NP_116030.1	Q99619-1
SPSB2	NM_001146316.2 link	c.445G>A	p.Ala149Thr	missense_variant	Exon 2 of 3		NP_001139788.1	Q99619-1
SPSB2	NM_001319670.2 link	c.445G>A	p.Ala149Thr	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.445G>A	p.Ala149Thr	missense_variant	Exon 2 of 3	1	NM_032641.4	ENSP00000428338.1	Q99619-1
SPSB2	ENST00000523102.5 link	c.445G>A	p.Ala149Thr	missense_variant	Exon 2 of 3	1		ENSP00000430872.1	Q99619-1
SPSB2	ENST00000519357.1 link	c.445G>A	p.Ala149Thr	missense_variant	Exon 2 of 2	2		ENSP00000431037.1	Q99619-2
SPSB2	ENST00000432205.5 link	c.*198G>A		downstream_gene_variant		3		ENSP00000428458.1	E5RIC2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251172

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

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:

0.0000831

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.445G>A (p.A149T) alteration is located in exon 2 (coding exon 1) of the SPSB2 gene. This alteration results from a G to A substitution at nucleotide position 445, causing the alanine (A) at amino acid position 149 to be replaced by a threonine (T). 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

0.091

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.091

T;T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.76

.;T;T

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.079

T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.23

N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.77

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.28

T;T;T

Sift4G

Benign

0.75

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.29

MutPred

0.40

Gain of catalytic residue at K145 (P = 0);Gain of catalytic residue at K145 (P = 0);Gain of catalytic residue at K145 (P = 0);

MVP

0.56

MPC

0.70

ClinPred

0.14

GERP RS

3.9

Varity_R

0.22

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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