Genetic Variant FCGR2A:p.Leu274Arg (chr1-161518015-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001136219.3(FCGR2A):c.821T>G(p.Leu274Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,371,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

FCGR2A
NM_001136219.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.131

Publications

23 publications found

Variant links:

Genes affected

FCGR2A (HGNC:3616): (Fc gamma receptor IIa) This gene encodes one member of a family of immunoglobulin Fc receptor genes found on the surface of many immune response cells. The protein encoded by this gene is a cell surface receptor found on phagocytic cells such as macrophages and neutrophils, and is involved in the process of phagocytosis and clearing of immune complexes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2008]

FCGR2A links:

ENSG00000273112 (HGNC:):

ENSG00000273112 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05073127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCGR2A	NM_001136219.3 link	c.821T>G	p.Leu274Arg	missense_variant	Exon 7 of 7	ENST00000271450.12	NP_001129691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCGR2A	ENST00000271450.12 link	c.821T>G	p.Leu274Arg	missense_variant	Exon 7 of 7	1	NM_001136219.3	ENSP00000271450.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000417

AC:

AN:

239870

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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

AF:

0.00000365

AC:

AN:

1371256

Hom.:

Cov.:

AF XY:

0.00000294

AC XY:

AN XY:

679912

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30930

American (AMR)

AF:

0.00

AC:

AN:

38390

Ashkenazi Jewish (ASJ)

AF:

0.0000441

AC:

AN:

22688

East Asian (EAS)

AF:

0.00

AC:

AN:

34834

South Asian (SAS)

AF:

0.0000128

AC:

AN:

78030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5340

European-Non Finnish (NFE)

AF:

0.00000283

AC:

AN:

1058616

Other (OTH)

AF:

0.00

AC:

AN:

55280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000805303), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.365

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.4

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.050

.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.051

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

.;N

PhyloP100

-0.13

PrimateAI

Benign

0.39

PROVEAN

Benign

0.010

N;N

REVEL

Benign

0.092

Sift

Benign

0.055

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.068

B;B

Vest4

0.20

MutPred

0.37

.;Loss of catalytic residue at L274 (P = 0.0139);

MVP

0.22

MPC

2.3

ClinPred

0.053

GERP RS

-1.4

Varity_R

0.18

gMVP

0.14

Mutation Taster

=100/0

polymorphism

(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