NM_001122681.2:c.276C>T

Variant names:

• chr4-2824649-C-T
• rs140326137
• NM_001122681.2:c.276C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001122681.2(SH3BP2):​c.276C>T​(p.Asn92Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,613,440 control chromosomes in the GnomAD database, including 463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (33 hom., cov: 33)
  • Exomes 𝑓: 0.022 (430 hom.)
• Consequence: SH3BP2 NM_001122681.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.11
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 4-2824649-C-T is Benign according to our data. Variant chr4-2824649-C-T is described in ClinVar as Benign. ClinVar VariationId is 348569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0155 (2367/152294) while in subpopulation NFE AF = 0.0247 (1679/68008). AF 95% confidence interval is 0.0237. There are 33 homozygotes in GnomAd4. There are 1079 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2367 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.276C>T	p.Asn92Asn	synonymous	Exon 4 of 13	NP_001116153.1	A0A384N6E5
	SH3BP2	NM_001145856.2		c.447C>T	p.Asn149Asn	synonymous	Exon 4 of 13	NP_001139328.1	P78314-4
	SH3BP2	NM_001145855.2		c.360C>T	p.Asn120Asn	synonymous	Exon 4 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.276C>T	p.Asn92Asn	synonymous	Exon 4 of 13	ENSP00000422168.3	P78314-1
	SH3BP2	ENST00000511747.6	TSL:1	c.447C>T	p.Asn149Asn	synonymous	Exon 4 of 13	ENSP00000424846.2	P78314-4
	SH3BP2	ENST00000356331.10	TSL:1	n.537C>T		non_coding_transcript_exon	Exon 4 of 13

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2367 AN: 152176 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0143 AC: 3596 AN: 251134 AF XY: 0.0142

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.00960

Gnomad ASJ exome AF: 0.00715

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0219 AC: 31938 AN: 1461146 Hom.: 430 Cov.: 31 AF XY: 0.0211 AC XY: 15346 AN XY: 726926

African (AFR) AF: 0.00355 AC: 119 AN: 33476

American (AMR) AF: 0.00977 AC: 437 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00700 AC: 183 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00262 AC: 226 AN: 86258

European-Finnish (FIN) AF: 0.0136 AC: 727 AN: 53284

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.0262 AC: 29161 AN: 1111432

Other (OTH) AF: 0.0172 AC: 1041 AN: 60378

GnomAD4 genome AF: 0.0155 AC: 2367 AN: 152294 Hom.: 33 Cov.: 33 AF XY: 0.0145 AC XY: 1079 AN XY: 74474

African (AFR) AF: 0.00602 AC: 250 AN: 41560

American (AMR) AF: 0.0150 AC: 229 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0247 AC: 1679 AN: 68008

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0188 Hom.: 13

Bravo AF: 0.0151

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0266

EpiControl AF: 0.0250

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fibrous dysplasia of jaw (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140326137; hg19: chr4-2826376; COSMIC: COSV62554155; COSMIC: COSV62554155;