NM_001122681.2:c.801C>T

Variant names:

• chr4-2829707-C-T
• rs114926004
• NM_001122681.2:c.801C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001122681.2(SH3BP2):​c.801C>T​(p.Cys267Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,612,774 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (26 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (26 hom.)
• Consequence: SH3BP2 NM_001122681.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.374
• 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), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-2829707-C-T is Benign according to our data. Variant chr4-2829707-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 525203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.374 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1530/152162) while in subpopulation AFR AF = 0.035 (1453/41496). AF 95% confidence interval is 0.0335. There are 26 homozygotes in GnomAd4. There are 730 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1530 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.801C>T	p.Cys267Cys	synonymous	Exon 8 of 13	NP_001116153.1
	SH3BP2	NM_001145856.2		c.972C>T	p.Cys324Cys	synonymous	Exon 8 of 13	NP_001139328.1
	SH3BP2	NM_001145855.2		c.885C>T	p.Cys295Cys	synonymous	Exon 8 of 13	NP_001139327.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.801C>T	p.Cys267Cys	synonymous	Exon 8 of 13	ENSP00000422168.3
	SH3BP2	ENST00000511747.6	TSL:1	c.972C>T	p.Cys324Cys	synonymous	Exon 8 of 13	ENSP00000424846.2
	SH3BP2	ENST00000356331.10	TSL:1	n.1062C>T		non_coding_transcript_exon	Exon 8 of 13

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1528 AN: 152044 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

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: 0.000162

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00249 AC: 621 AN: 249676 AF XY: 0.00177

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000958 AC: 1399 AN: 1460612 Hom.: 26 Cov.: 36 AF XY: 0.000842 AC XY: 612 AN XY: 726652

African (AFR) AF: 0.0333 AC: 1115 AN: 33472

American (AMR) AF: 0.00179 AC: 80 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52476

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0000585 AC: 65 AN: 1111746

Other (OTH) AF: 0.00220 AC: 133 AN: 60366

GnomAD4 genome AF: 0.0101 AC: 1530 AN: 152162 Hom.: 26 Cov.: 33 AF XY: 0.00981 AC XY: 730 AN XY: 74380

African (AFR) AF: 0.0350 AC: 1453 AN: 41496

American (AMR) AF: 0.00320 AC: 49 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67986

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00687 Hom.: 8

Bravo AF: 0.0114

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fibrous dysplasia of jaw (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.41
PhyloP100		-0.37
PromoterAI		0.0022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism

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: rs114926004; hg19: chr4-2831434;