Genetic Variant SPSB2:p.His119Arg (chr12-6872546-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032641.4(SPSB2):c.356A>G(p.His119Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,458,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

SPSB2
NM_032641.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.80

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060872853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPSB2	NM_032641.4 link	c.356A>G	p.His119Arg	missense_variant	Exon 2 of 3	ENST00000524270.6	NP_116030.1	Q99619-1
SPSB2	NM_001146316.2 link	c.356A>G	p.His119Arg	missense_variant	Exon 2 of 3		NP_001139788.1	Q99619-1
SPSB2	NM_001319670.2 link	c.356A>G	p.His119Arg	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.356A>G	p.His119Arg	missense_variant	Exon 2 of 3	1	NM_032641.4	ENSP00000428338.1	Q99619-1
SPSB2	ENST00000523102.5 link	c.356A>G	p.His119Arg	missense_variant	Exon 2 of 3	1		ENSP00000430872.1	Q99619-1
SPSB2	ENST00000519357.1 link	c.356A>G	p.His119Arg	missense_variant	Exon 2 of 2	2		ENSP00000431037.1	Q99619-2
SPSB2	ENST00000432205.5 link	c.*109A>G		downstream_gene_variant		3		ENSP00000428458.1	E5RIC2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000405

AC:

AN:

246712

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

134100

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000548

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:

0.00000686

AC:

AN:

1458504

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725694

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

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

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.356A>G (p.H119R) alteration is located in exon 2 (coding exon 1) of the SPSB2 gene. This alteration results from a A to G substitution at nucleotide position 356, causing the histidine (H) at amino acid position 119 to be replaced by an arginine (R). 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

0.084

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.58

CADD

Uncertain

DANN

Benign

0.63

DEOGEN2

Benign

0.15

T;T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.65

.;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.061

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.69

N;N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.26

N;N;N

REVEL

Benign

0.081

Sift

Benign

0.14

T;T;T

Sift4G

Uncertain

0.057

T;T;T

Polyphen

0.20

B;B;.

Vest4

0.41

MVP

0.16

MPC

0.32

ClinPred

0.031

GERP RS

1.5

Varity_R

0.13

gMVP

0.46

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

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