22-37228959-A-G

Variant names:

• chr22-37228959-A-G
• rs739041
• NM_002872.5:c.449-2156T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002872.5(RAC2):​c.449-2156T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 152,060 control chromosomes in the GnomAD database, including 16,099 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (16099 hom., cov: 33)
• Consequence: RAC2 NM_002872.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.251
• Publications: 13 publications found

Genes affected

RAC2 (HGNC:9802): (Rac family small GTPase 2) This gene encodes a member of the Ras superfamily of small guanosine triphosphate (GTP)-metabolizing proteins. The encoded protein localizes to the plasma membrane, where it regulates diverse processes, such as secretion, phagocytosis, and cell polarization. Activity of this protein is also involved in the generation of reactive oxygen species. Mutations in this gene are associated with neutrophil immunodeficiency syndrome. There is a pseudogene for this gene on chromosome 6. [provided by RefSeq, Jul 2013]

RAC2 Gene-Disease associations (from GenCC):

• immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• neutrophil immunodeficiency syndrome

  Inheritance: AD, Unknown Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002872.5. 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
	RAC2	NM_002872.5	MANE Select	c.449-2156T>C		intron	N/A	NP_002863.1	P15153

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAC2	ENST00000249071.11	TSL:1 MANE Select	c.449-2156T>C		intron	N/A	ENSP00000249071.6	P15153
	RAC2	ENST00000481215.1	TSL:1	n.274-2156T>C		intron	N/A
	RAC2	ENST00000870381.1		c.449-2156T>C		intron	N/A	ENSP00000540440.1

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68563 AN: 151942 Hom.: 16062 Cov.: 33

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.452

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.451 AC: 68654 AN: 152060 Hom.: 16099 Cov.: 33 AF XY: 0.446 AC XY: 33141 AN XY: 74316

African (AFR) AF: 0.587 AC: 24361 AN: 41488

American (AMR) AF: 0.382 AC: 5843 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1553 AN: 3470

East Asian (EAS) AF: 0.418 AC: 2159 AN: 5170

South Asian (SAS) AF: 0.377 AC: 1819 AN: 4824

European-Finnish (FIN) AF: 0.350 AC: 3701 AN: 10586

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.410 AC: 27833 AN: 67928

Other (OTH) AF: 0.453 AC: 953 AN: 2106

Alfa AF: 0.414 Hom.: 7065

Bravo AF: 0.459

Asia WGS AF: 0.408 AC: 1418 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.0
DANN	Benign	0.89
PhyloP100		-0.25
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: rs739041; hg19: chr22-37624999; COSMIC: COSV50774760; COSMIC: COSV50774760;