12-6872345-T-G

Variant names:

• chr12-6872345-T-G
• rs782555852
• NM_032641.4:c.557A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032641.4(SPSB2):​c.557A>C​(p.Tyr186Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPSB2 NM_032641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.99

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPSB2	NM_032641.4	c.557A>C	p.Tyr186Ser	missense_variant	Exon 2 of 3	ENST00000524270.6	NP_116030.1
SPSB2	NM_001146316.2	c.557A>C	p.Tyr186Ser	missense_variant	Exon 2 of 3		NP_001139788.1
SPSB2	NM_001319670.2	c.557A>C	p.Tyr186Ser	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.557A>C	p.Tyr186Ser	missense_variant	Exon 2 of 3	1	NM_032641.4	ENSP00000428338.1
SPSB2	ENST00000523102.5	c.557A>C	p.Tyr186Ser	missense_variant	Exon 2 of 3	1		ENSP00000430872.1
SPSB2	ENST00000519357.1	c.557A>C	p.Tyr186Ser	missense_variant	Exon 2 of 2	2		ENSP00000431037.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.74	.;T;T
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.4	D;D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.77
MutPred		0.61		Gain of catalytic residue at Y186 (P = 0);Gain of catalytic residue at Y186 (P = 0);Gain of catalytic residue at Y186 (P = 0);
MVP		0.43
MPC		1.0
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.97
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs782555852; hg19: chr12-6981509;