Genetic Variant NM_032641.4:c.770A>G (chr12-6871214-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032641.4(SPSB2):c.770A>G(p.Lys257Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000193 in 1,608,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SPSB2
NM_032641.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.18

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPSB2	NM_032641.4 link	c.770A>G	p.Lys257Arg	missense_variant	Exon 3 of 3	ENST00000524270.6	NP_116030.1	Q99619-1
SPSB2	NM_001146316.2 link	c.770A>G	p.Lys257Arg	missense_variant	Exon 3 of 3		NP_001139788.1	Q99619-1
SPSB2	NM_001319670.2 link	c.770A>G	p.Lys257Arg	missense_variant	Exon 2 of 2		NP_001306599.1	Q99619-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPSB2	ENST00000524270.6 link	c.770A>G	p.Lys257Arg	missense_variant	Exon 3 of 3	1	NM_032641.4	ENSP00000428338.1		Q99619-1
SPSB2	ENST00000523102.5 link	c.770A>G	p.Lys257Arg	missense_variant	Exon 3 of 3	1		ENSP00000430872.1		Q99619-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

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

GnomAD3 exomes

AF:

0.0000418

AC:

AN:

239446

Hom.:

AF XY:

0.0000308

AC XY:

AN XY:

129860

show subpopulations

Gnomad AFR exome

AF:

0.000525

Gnomad AMR exome

AF:

0.00

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:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1456690

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

724236

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00

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:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.000338

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

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.770A>G (p.K257R) alteration is located in exon 3 (coding exon 2) of the SPSB2 gene. This alteration results from a A to G substitution at nucleotide position 770, causing the lysine (K) at amino acid position 257 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

0.12

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.85

.;D

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.5

L;L

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.066

T;T

Sift4G

Benign

0.15

T;T

Polyphen

1.0

D;D

Vest4

0.65

MVP

0.46

MPC

0.76

ClinPred

0.20

GERP RS

3.9

Varity_R

0.12

gMVP

0.39

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

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