4-2818442-C-G

Variant names:

• chr4-2818442-C-G
• rs28507721
• NM_001122681.2:c.-4-2172C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001122681.2(SH3BP2):​c.-4-2172C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 1,006,900 control chromosomes in the GnomAD database, including 5,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (855 hom., cov: 33)
  • Exomes 𝑓: 0.098 (4260 hom.)
• Consequence: SH3BP2 NM_001122681.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.83
• 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), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-2818442-C-G is Benign according to our data. Variant chr4-2818442-C-G is described in ClinVar as [Benign]. Clinvar id is 1226123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.-4-2172C>G		intron_variant	Intron 1 of 12	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.167+52C>G		intron_variant	Intron 1 of 12		NP_001139328.1
SH3BP2	NM_001145855.2	c.81-2172C>G		intron_variant	Intron 1 of 12		NP_001139327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.-4-2172C>G		intron_variant	Intron 1 of 12	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15351 AN: 151474 Hom.: 855 Cov.: 33

Gnomad AFR AF: 0.0913

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.0832

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.0921

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.0984 AC: 84147 AN: 855320 Hom.: 4260 AF XY: 0.0990 AC XY: 40076 AN XY: 404970

African (AFR) AF: 0.0955 AC: 1661 AN: 17400

American (AMR) AF: 0.0567 AC: 327 AN: 5770

Ashkenazi Jewish (ASJ) AF: 0.0924 AC: 969 AN: 10492

East Asian (EAS) AF: 0.00444 AC: 91 AN: 20500

South Asian (SAS) AF: 0.101 AC: 1591 AN: 15780

European-Finnish (FIN) AF: 0.169 AC: 2833 AN: 16790

Middle Eastern (MID) AF: 0.136 AC: 303 AN: 2222

European-Non Finnish (NFE) AF: 0.100 AC: 73352 AN: 732972

Other (OTH) AF: 0.0904 AC: 3020 AN: 33394

GnomAD4 genome AF: 0.101 AC: 15352 AN: 151580 Hom.: 855 Cov.: 33 AF XY: 0.103 AC XY: 7662 AN XY: 74086

African (AFR) AF: 0.0912 AC: 3780 AN: 41462

American (AMR) AF: 0.0705 AC: 1075 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0832 AC: 288 AN: 3462

East Asian (EAS) AF: 0.0109 AC: 56 AN: 5150

South Asian (SAS) AF: 0.0922 AC: 444 AN: 4818

European-Finnish (FIN) AF: 0.181 AC: 1890 AN: 10420

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.110 AC: 7464 AN: 67712

Other (OTH) AF: 0.105 AC: 221 AN: 2102

Alfa AF: 0.0519 Hom.: 75

Bravo AF: 0.0915

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.3
DANN	Benign	0.21
PhyloP100		-1.8
PromoterAI		-0.36	Neutral
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: rs28507721; hg19: chr4-2820169;