NM_002872.5:c.252C>T

Variant names:

• chr22-37231968-G-A
• rs2230919
• NM_002872.5:c.252C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002872.5(RAC2):​c.252C>T​(p.Leu84Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00427 in 1,552,320 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L84L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (71 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (52 hom.)
• Consequence: RAC2 NM_002872.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.57
• Publications: 1 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
• immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia

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

  Inheritance: Unknown, AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 22-37231968-G-A is Benign according to our data. Variant chr22-37231968-G-A is described in ClinVar as Benign. ClinVar VariationId is 378454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAC2	NM_002872.5	MANE Select	c.252C>T	p.Leu84Leu	synonymous	Exon 4 of 7	NP_002863.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAC2	ENST00000249071.11	TSL:1 MANE Select	c.252C>T	p.Leu84Leu	synonymous	Exon 4 of 7	ENSP00000249071.6
	RAC2	ENST00000870381.1		c.252C>T	p.Leu84Leu	synonymous	Exon 4 of 7	ENSP00000540440.1
	RAC2	ENST00000870383.1		c.252C>T	p.Leu84Leu	synonymous	Exon 4 of 6	ENSP00000540442.1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2844 AN: 152024 Hom.: 71 Cov.: 31

Gnomad AFR AF: 0.0617

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00950

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00510 AC: 804 AN: 157696 AF XY: 0.00420

Gnomad AFR exome AF: 0.0628

Gnomad AMR exome AF: 0.00479

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000850

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00269 AC: 3763 AN: 1400178 Hom.: 52 Cov.: 31 AF XY: 0.00248 AC XY: 1710 AN XY: 690708

African (AFR) AF: 0.0608 AC: 1923 AN: 31624

American (AMR) AF: 0.00514 AC: 184 AN: 35806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.0000559 AC: 2 AN: 35786

South Asian (SAS) AF: 0.000378 AC: 30 AN: 79268

European-Finnish (FIN) AF: 0.00122 AC: 60 AN: 49220

Middle Eastern (MID) AF: 0.00614 AC: 35 AN: 5696

European-Non Finnish (NFE) AF: 0.00114 AC: 1227 AN: 1079536

Other (OTH) AF: 0.00520 AC: 302 AN: 58058

GnomAD4 genome AF: 0.0188 AC: 2861 AN: 152142 Hom.: 71 Cov.: 31 AF XY: 0.0188 AC XY: 1399 AN XY: 74374

African (AFR) AF: 0.0619 AC: 2567 AN: 41480

American (AMR) AF: 0.00948 AC: 145 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4810

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00152 AC: 103 AN: 67986

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00807 Hom.: 18

Bravo AF: 0.0210

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Neutrophil immunodeficiency syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	4.8
DANN	Benign	0.78
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2230919; hg19: chr22-37628008;