12-6872565-C-G

Variant names:

• chr12-6872565-C-G
• NM_032641.4:c.337G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032641.4(SPSB2):​c.337G>C​(p.Ala113Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPSB2 NM_032641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPSB2	NM_032641.4	c.337G>C	p.Ala113Pro	missense_variant	Exon 2 of 3	ENST00000524270.6	NP_116030.1
SPSB2	NM_001146316.2	c.337G>C	p.Ala113Pro	missense_variant	Exon 2 of 3		NP_001139788.1
SPSB2	NM_001319670.2	c.337G>C	p.Ala113Pro	missense_variant	Exon 1 of 2		NP_001306599.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPSB2	ENST00000524270.6	c.337G>C	p.Ala113Pro	missense_variant	Exon 2 of 3	1	NM_032641.4	ENSP00000428338.1
SPSB2	ENST00000523102.5	c.337G>C	p.Ala113Pro	missense_variant	Exon 2 of 3	1		ENSP00000430872.1
SPSB2	ENST00000519357.1	c.337G>C	p.Ala113Pro	missense_variant	Exon 2 of 2	2		ENSP00000431037.1
SPSB2	ENST00000432205.5	c.*90G>C		downstream_gene_variant		3		ENSP00000428458.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.337G>C (p.A113P) alteration is located in exon 2 (coding exon 1) of the SPSB2 gene. This alteration results from a G to C substitution at nucleotide position 337, causing the alanine (A) at amino acid position 113 to be replaced by a proline (P). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	.;D;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.8	H;H;H
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.69
MutPred		0.72		Gain of catalytic residue at Q116 (P = 2e-04);Gain of catalytic residue at Q116 (P = 2e-04);Gain of catalytic residue at Q116 (P = 2e-04);
MVP		0.61
MPC		0.97
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.93
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-6981729;