dbSNP rs200506549: PLCG2:p.Thr329Thr (chr16-81893709-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is The variant received -11 classification points (ACMG Germline Pathogenicity v2019). BS2BP4_ModerateBP6_StrongBP7

The NM_002661.5(PLCG2):c.987G>A (p.Thr329Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00128 (AC=2,050) in the gnomAD database across 1,607,178 control chromosomes, including 5 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00569. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

PLCG2
NM_002661.5 splice_region, synonymous

Scores

Splicing: ADA: 0.0009308

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.11

Publications

4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet
familial cold autoinflammatory syndrome 3
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, G2P

PLCG2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002661.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -11 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BP7

Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

BS2

≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 5.; Very high cumulative gnomAD AC = 2050 (any gene).

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCG2	NM_002661.5	MANE Select	c.987G>A	p.Thr329Thr	splice_region synonymous	Exon 12 of 33	NP_002652.2	P16885
PLCG2	NM_001425749.1		c.987G>A	p.Thr329Thr	splice_region synonymous	Exon 13 of 34	NP_001412678.1	P16885
PLCG2	NM_001425750.1		c.987G>A	p.Thr329Thr	splice_region synonymous	Exon 12 of 33	NP_001412679.1	P16885

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.987G>A	p.Thr329Thr	splice_region synonymous	Exon 12 of 33	ENSP00000482457.1	P16885
PLCG2	ENST00000567980.5	TSL:1	n.1231G>A		splice_region non_coding_transcript_exon	Exon 11 of 20
PLCG2	ENST00000902427.1		c.987G>A	p.Thr329Thr	splice_region synonymous	Exon 12 of 34	ENSP00000572486.1	A0ACI8QWA4

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

246

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.0451

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00129

AC:

320

AN:

247740

AF XY:

0.00143

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.00269

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000488

Gnomad NFE exome

AF:

0.00187

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00124

AC:

1804

AN:

1454914

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

967

AN XY:

724286

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

33366

American (AMR)

AF:

0.00134

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00241

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.000349

AC:

AN:

86058

European-Finnish (FIN)

AF:

0.0000577

AC:

AN:

51992

Middle Eastern (MID)

AF:

0.00747

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00136

AC:

1511

AN:

1107126

Other (OTH)

AF:

0.00138

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

171

257

342

428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.00162

AC:

246

AN:

152264

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41568

American (AMR)

AF:

0.00353

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00181

AC:

123

AN:

68028

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00752

Hom.:

835

Bravo

AF:

0.00180

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00344

EpiControl

AF:

0.00220

Local populations

Turkish Variome

AF:

0.00646

AC:

AN:

6656

Hom.:

ABraOM SABE-WGS-1171

AF:

0.00256

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Familial cold autoinflammatory syndrome 3 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

1.1

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00093

dbscSNV1_RF

Benign

0.18

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over