Genetic Variant PLCG2:p.Ala499Ala (chr16-81907714-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002661.5(PLCG2):c.1497C>T(p.Ala499Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,612,556 control chromosomes in the GnomAD database, including 474,023 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. A499A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.74 ( 42012 hom., cov: 32)

Exomes 𝑓: 0.77 ( 432011 hom. )

Consequence

PLCG2
NM_002661.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -3.15

Publications

23 publications found

Variant links:

Genes affected

PLCG2 (HGNC:9066): (phospholipase C gamma 2) The protein encoded by this gene is a transmembrane signaling enzyme that catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to 1D-myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) using calcium as a cofactor. IP3 and DAG are second messenger molecules important for transmitting signals from growth factor receptors and immune system receptors across the cell membrane. Mutations in this gene have been found in autoinflammation, antibody deficiency, and immune dysregulation syndrome and familial cold autoinflammatory syndrome 3. [provided by RefSeq, Mar 2014]

PLCG2 Gene-Disease associations (from GenCC):

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
familial cold autoinflammatory syndrome 3
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

PLCG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 16-81907714-C-T is Benign according to our data. Variant chr16-81907714-C-T is described in ClinVar as Benign. ClinVar VariationId is 403322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.15 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002661.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCG2	NM_002661.5	MANE Select	c.1497C>T	p.Ala499Ala	synonymous	Exon 16 of 33	NP_002652.2
PLCG2	NM_001425749.1		c.1497C>T	p.Ala499Ala	synonymous	Exon 17 of 34	NP_001412678.1
PLCG2	NM_001425750.1		c.1497C>T	p.Ala499Ala	synonymous	Exon 16 of 33	NP_001412679.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.1497C>T	p.Ala499Ala	synonymous	Exon 16 of 33	ENSP00000482457.1
PLCG2	ENST00000567980.5	TSL:1	n.1741C>T		non_coding_transcript_exon	Exon 15 of 20
PLCG2	ENST00000902427.1		c.1650C>T	p.Ala550Ala	synonymous	Exon 17 of 34	ENSP00000572486.1

Frequencies

GnomAD3 genomes

AF:

0.736

AC:

111910

AN:

151968

Hom.:

41981

Cov.:

show subpopulations

Gnomad AFR

AF:

0.603

Gnomad AMI

AF:

0.761

Gnomad AMR

AF:

0.844

Gnomad ASJ

AF:

0.771

Gnomad EAS

AF:

0.969

Gnomad SAS

AF:

0.805

Gnomad FIN

AF:

0.743

Gnomad MID

AF:

0.801

Gnomad NFE

AF:

0.766

Gnomad OTH

AF:

0.778

GnomAD2 exomes

AF:

0.789

AC:

196783

AN:

249382

AF XY:

0.788

show subpopulations

Gnomad AFR exome

AF:

0.597

Gnomad AMR exome

AF:

0.893

Gnomad ASJ exome

AF:

0.779

Gnomad EAS exome

AF:

0.971

Gnomad FIN exome

AF:

0.743

Gnomad NFE exome

AF:

0.765

Gnomad OTH exome

AF:

0.792

GnomAD4 exome

AF:

0.767

AC:

1120409

AN:

1460470

Hom.:

432011

Cov.:

AF XY:

0.768

AC XY:

558089

AN XY:

726592

show subpopulations

African (AFR)

AF:

0.601

AC:

20082

AN:

33442

American (AMR)

AF:

0.886

AC:

39613

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.782

AC:

20411

AN:

26114

East Asian (EAS)

AF:

0.968

AC:

38442

AN:

39696

South Asian (SAS)

AF:

0.788

AC:

67901

AN:

86202

European-Finnish (FIN)

AF:

0.746

AC:

39854

AN:

53388

Middle Eastern (MID)

AF:

0.802

AC:

4612

AN:

5748

European-Non Finnish (NFE)

AF:

0.759

AC:

843128

AN:

1110832

Other (OTH)

AF:

0.769

AC:

46366

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

12377

24754

37131

49508

61885

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20380

40760

61140

81520

101900

<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

AF:

0.736

AC:

111993

AN:

152086

Hom.:

42012

Cov.:

AF XY:

0.740

AC XY:

55007

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.603

AC:

25023

AN:

41466

American (AMR)

AF:

0.844

AC:

12920

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.771

AC:

2676

AN:

3470

East Asian (EAS)

AF:

0.969

AC:

4995

AN:

5156

South Asian (SAS)

AF:

0.805

AC:

3878

AN:

4818

European-Finnish (FIN)

AF:

0.743

AC:

7870

AN:

10596

Middle Eastern (MID)

AF:

0.806

AC:

237

AN:

294

European-Non Finnish (NFE)

AF:

0.766

AC:

52052

AN:

67956

Other (OTH)

AF:

0.780

AC:

1648

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1464

2927

4391

5854

7318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

838

1676

2514

3352

4190

<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:

0.761

Hom.:

102863

Bravo

AF:

0.738

EpiCase

AF:

0.766

EpiControl

AF:

0.771

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Familial cold autoinflammatory syndrome 3 (2)

not provided (3)

Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.13

(source)

DANN

Benign

0.68

PhyloP100

-3.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over