rs231402

Variant names:

• chr4-2820740-G-T
• rs231402
• NM_001122681.2:c.123G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001122681.2(SH3BP2):​c.123G>T​(p.Leu41Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 1,612,980 control chromosomes in the GnomAD database, including 161,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (12158 hom., cov: 34)
  • Exomes 𝑓: 0.45 (149136 hom.)
• Consequence: SH3BP2 NM_001122681.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 2.21
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-2820740-G-T is Benign according to our data. Variant chr4-2820740-G-T is described in ClinVar as Benign. ClinVar VariationId is 258893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

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.123G>T	p.Leu41Leu	synonymous	Exon 2 of 13	NP_001116153.1	A0A384N6E5
	SH3BP2	NM_001145856.2		c.294G>T	p.Leu98Leu	synonymous	Exon 2 of 13	NP_001139328.1	P78314-4
	SH3BP2	NM_001145855.2		c.207G>T	p.Leu69Leu	synonymous	Exon 2 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.123G>T	p.Leu41Leu	synonymous	Exon 2 of 13	ENSP00000422168.3	P78314-1
	SH3BP2	ENST00000511747.6	TSL:1	c.294G>T	p.Leu98Leu	synonymous	Exon 2 of 13	ENSP00000424846.2	P78314-4
	SH3BP2	ENST00000356331.10	TSL:1	n.384G>T		non_coding_transcript_exon	Exon 2 of 13

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56862 AN: 152064 Hom.: 12148 Cov.: 34

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.615

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.381

GnomAD2 exomes AF: 0.453 AC: 112803 AN: 249080 AF XY: 0.455

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.605

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.439

Gnomad NFE exome AF: 0.448

Gnomad OTH exome AF: 0.455

GnomAD4 exome AF: 0.447 AC: 653342 AN: 1460798 Hom.: 149136 Cov.: 49 AF XY: 0.449 AC XY: 325965 AN XY: 726656

African (AFR) AF: 0.142 AC: 4766 AN: 33476

American (AMR) AF: 0.597 AC: 26579 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 10667 AN: 26118

East Asian (EAS) AF: 0.456 AC: 18075 AN: 39674

South Asian (SAS) AF: 0.493 AC: 42511 AN: 86234

European-Finnish (FIN) AF: 0.441 AC: 23521 AN: 53330

Middle Eastern (MID) AF: 0.394 AC: 2265 AN: 5756

European-Non Finnish (NFE) AF: 0.449 AC: 498705 AN: 1111340

Other (OTH) AF: 0.435 AC: 26253 AN: 60356

GnomAD4 genome AF: 0.374 AC: 56881 AN: 152182 Hom.: 12158 Cov.: 34 AF XY: 0.380 AC XY: 28243 AN XY: 74394

African (AFR) AF: 0.153 AC: 6351 AN: 41536

American (AMR) AF: 0.517 AC: 7908 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1401 AN: 3468

East Asian (EAS) AF: 0.463 AC: 2394 AN: 5170

South Asian (SAS) AF: 0.496 AC: 2391 AN: 4822

European-Finnish (FIN) AF: 0.438 AC: 4642 AN: 10604

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30288 AN: 67980

Other (OTH) AF: 0.383 AC: 807 AN: 2106

Alfa AF: 0.413 Hom.: 13036

Bravo AF: 0.372

Asia WGS AF: 0.477 AC: 1658 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fibrous dysplasia of jaw (3)
-	-	3	not specified (3)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.6
DANN	Benign	0.79
PhyloP100		2.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs231402; hg19: chr4-2822467; COSMIC: COSV62553730; COSMIC: COSV62553730;