Genetic Variant NM_001122681.2:c.1666G>C (chr4-2833814-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001122681.2(SH3BP2):c.1666G>C(p.Gly556Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000701 in 1,427,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G556S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SH3BP2
NM_001122681.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.24

Publications

1 publications found

Variant links:

Genes affected

SH3BP2 (HGNC:10825): (SH3 domain binding protein 2) The protein encoded by this gene has an N-terminal pleckstrin homology (PH) domain, an SH3-binding proline-rich region, and a C-terminal SH2 domain. The protein binds to the SH3 domains of several proteins including the ABL1 and SYK protein tyrosine kinases , and functions as a cytoplasmic adaptor protein to positively regulate transcriptional activity in T, natural killer (NK), and basophilic cells. Mutations in this gene result in cherubism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

SH3BP2 Gene-Disease associations (from GenCC):

cherubism
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

SH3BP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SH3BP2	NM_001122681.2	MANE Select	c.1666G>C	p.Gly556Arg	missense	Exon 13 of 13	NP_001116153.1
SH3BP2	NM_001145856.2		c.1837G>C	p.Gly613Arg	missense	Exon 13 of 13	NP_001139328.1
SH3BP2	NM_001145855.2		c.1750G>C	p.Gly584Arg	missense	Exon 13 of 13	NP_001139327.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.1666G>C	p.Gly556Arg	missense	Exon 13 of 13	ENSP00000422168.3
SH3BP2	ENST00000511747.6	TSL:1	c.1837G>C	p.Gly613Arg	missense	Exon 13 of 13	ENSP00000424846.2
SH3BP2	ENST00000356331.10	TSL:1	n.1927G>C		non_coding_transcript_exon	Exon 13 of 13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1427040

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

707240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32676

American (AMR)

AF:

0.00

AC:

AN:

40246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25548

East Asian (EAS)

AF:

0.00

AC:

AN:

37864

South Asian (SAS)

AF:

0.00

AC:

AN:

82306

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5498

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1095046

Other (OTH)

AF:

0.00

AC:

AN:

59060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.0

PhyloP100

5.2

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.62

MutPred

0.60

Gain of MoRF binding (P = 0.0019)

MVP

0.94

MPC

0.75

ClinPred

0.96

GERP RS

5.6

Varity_R

0.34

Mutation Taster

=38/62

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over