chr22-37226707-G-C

Variant names:

• chr22-37226707-G-C
• rs141308774
• NM_002872.5:c.545C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002872.5(RAC2):​c.545C>G​(p.Thr182Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T182M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAC2 NM_002872.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.592 (below the threshold of 3.09). Trascript score misZ: 2.9101 (below the threshold of 3.09). GenCC associations: The gene is linked to immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, neutrophil immunodeficiency syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17681086).

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.545C>G	p.Thr182Arg	missense	Exon 6 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.545C>G	p.Thr182Arg	missense	Exon 6 of 7	ENSP00000249071.6
	RAC2	ENST00000481215.1	TSL:1	n.370C>G		non_coding_transcript_exon	Exon 2 of 3
	RAC2	ENST00000405484.5	TSL:3	c.524C>G	p.Thr175Arg	missense	Exon 6 of 6	ENSP00000385590.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249900 AF XY: 0.00

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.22	N
PhyloP100		3.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.23
Sift	Benign	0.55	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.41
MutPred		0.38		Gain of MoRF binding (P = 0.0146)
MVP		0.75
MPC		0.078
ClinPred		0.20	T
GERP RS		3.9
Varity_R		0.036
gMVP		0.72
Mutation Taster		=53/47	polymorphism

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: rs141308774; hg19: chr22-37622747;