Genetic Variant NM_002872.5:c.449-2156T>C (chr22-37228959-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.251

Publications

13 publications found

Variant links:

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)

RAC2 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC2	NM_002872.5 link	c.449-2156T>C		intron_variant	Intron 5 of 6	ENST00000249071.11	NP_002863.1	P15153A0A024R1P2V9H0H7
RAC2	XM_006724286.4 link	c.449-1016T>C		intron_variant	Intron 5 of 5		XP_006724349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAC2	ENST00000249071.11 link	c.449-2156T>C		intron_variant	Intron 5 of 6	1	NM_002872.5	ENSP00000249071.6		P15153

Frequencies

GnomAD3 genomes

AF:

0.451

AC:

68563

AN:

151942

Hom.:

16062

Cov.:

show subpopulations

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.:

AF XY:

0.446

AC XY:

33141

AN XY:

74316

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1937

3875

5812

7750

9687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

630

1260

1890

2520

3150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

9.0

(source)

DANN

Benign

0.89

PhyloP100

-0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over