chr4-2827661-C-G

Variant names:

• chr4-2827661-C-G
• rs755387801
• NM_001122681.2:c.573C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001122681.2(SH3BP2):​c.573C>G​(p.Pro191Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000067 in 1,344,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P191P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: SH3BP2 NM_001122681.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.57
• Publications: 0 publications found

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), Orphanet, G2P, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-2827661-C-G is Benign according to our data. Variant chr4-2827661-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1899469.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.57 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	NM_001122681.2	MANE Select	c.573C>G	p.Pro191Pro	synonymous	Exon 7 of 13	NP_001116153.1	A0A384N6E5
	SH3BP2	NM_001145856.2		c.744C>G	p.Pro248Pro	synonymous	Exon 7 of 13	NP_001139328.1	P78314-4
	SH3BP2	NM_001145855.2		c.657C>G	p.Pro219Pro	synonymous	Exon 7 of 13	NP_001139327.1	P78314-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.573C>G	p.Pro191Pro	synonymous	Exon 7 of 13	ENSP00000422168.3	P78314-1
	SH3BP2	ENST00000511747.6	TSL:1	c.744C>G	p.Pro248Pro	synonymous	Exon 7 of 13	ENSP00000424846.2	P78314-4
	SH3BP2	ENST00000356331.10	TSL:1	n.834C>G		non_coding_transcript_exon	Exon 7 of 13

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147072 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000301

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 209910 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000585 AC: 7 AN: 1197202 Hom.: 0 Cov.: 40 AF XY: 0.00000504 AC XY: 3 AN XY: 595814

African (AFR) AF: 0.00 AC: 0 AN: 29250

American (AMR) AF: 0.00 AC: 0 AN: 37450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19216

East Asian (EAS) AF: 0.00 AC: 0 AN: 24888

South Asian (SAS) AF: 0.00 AC: 0 AN: 79822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4814

European-Non Finnish (NFE) AF: 0.00000762 AC: 7 AN: 918142

Other (OTH) AF: 0.00 AC: 0 AN: 46662

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147072 Hom.: 0 Cov.: 34 AF XY: 0.0000139 AC XY: 1 AN XY: 71704

African (AFR) AF: 0.00 AC: 0 AN: 40892

American (AMR) AF: 0.00 AC: 0 AN: 14902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 4504

South Asian (SAS) AF: 0.00 AC: 0 AN: 4242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000301 AC: 2 AN: 66352

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Fibrous dysplasia of jaw (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.7
DANN	Benign	0.52
PhyloP100		-2.6

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

Other links and lift over

dbSNP: rs755387801; hg19: chr4-2829388;