NM_001122681.2:c.-4-52C>A

Variant names:

• chr4-2820562-C-A
• rs2239727
• NM_001122681.2:c.-4-52C>A

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.-4-52C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 1,611,824 control chromosomes in the GnomAD database, including 243,390 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (22984 hom., cov: 34)
  • Exomes 𝑓: 0.55 (220406 hom.)
• Consequence: SH3BP2 NM_001122681.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.32
• Publications: 7 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=-0.8).
• BP6: Variant 4-2820562-C-A is Benign according to our data. Variant chr4-2820562-C-A is described in ClinVar as [Benign]. Clinvar id is 1256910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.-4-52C>A		intron_variant	Intron 1 of 12	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.168-52C>A		intron_variant	Intron 1 of 12		NP_001139328.1
SH3BP2	NM_001145855.2	c.81-52C>A		intron_variant	Intron 1 of 12		NP_001139327.1
SH3BP2	NM_003023.4	c.-4-52C>A		intron_variant	Intron 1 of 12		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.-4-52C>A		intron_variant	Intron 1 of 12	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83259 AN: 152048 Hom.: 22959 Cov.: 34

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.639

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.544

GnomAD4 exome AF: 0.548 AC: 799673 AN: 1459656 Hom.: 220406 AF XY: 0.549 AC XY: 398552 AN XY: 726166

African (AFR) AF: 0.534 AC: 17863 AN: 33452

American (AMR) AF: 0.672 AC: 30050 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 14078 AN: 26098

East Asian (EAS) AF: 0.465 AC: 18446 AN: 39672

South Asian (SAS) AF: 0.597 AC: 51413 AN: 86154

European-Finnish (FIN) AF: 0.486 AC: 25887 AN: 53240

Middle Eastern (MID) AF: 0.568 AC: 3268 AN: 5758

European-Non Finnish (NFE) AF: 0.545 AC: 605523 AN: 1110294

Other (OTH) AF: 0.550 AC: 33145 AN: 60302

GnomAD4 genome AF: 0.548 AC: 83325 AN: 152168 Hom.: 22984 Cov.: 34 AF XY: 0.547 AC XY: 40694 AN XY: 74386

African (AFR) AF: 0.542 AC: 22488 AN: 41508

American (AMR) AF: 0.639 AC: 9763 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 1905 AN: 3468

East Asian (EAS) AF: 0.471 AC: 2435 AN: 5170

South Asian (SAS) AF: 0.588 AC: 2839 AN: 4826

European-Finnish (FIN) AF: 0.480 AC: 5087 AN: 10602

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.543 AC: 36889 AN: 67990

Other (OTH) AF: 0.546 AC: 1153 AN: 2112

Alfa AF: 0.536 Hom.: 2853

Bravo AF: 0.559

Asia WGS AF: 0.551 AC: 1914 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 88% of patients studied by a panel of primary immunodeficiencies. Number of patients: 84. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.7
DANN	Benign	0.75
PhyloP100		1.3
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: rs2239727; hg19: chr4-2822289; COSMIC: COSV62553770; COSMIC: COSV62553770;