dbSNP rs138158454: PLCG2:c.2054+7G>A (chr16-81912723-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002661.5(PLCG2):c.2054+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,592,502 control chromosomes in the GnomAD database, including 1,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 92 hom., cov: 33)

Exomes 𝑓: 0.041 ( 1390 hom. )

Consequence

PLCG2
NM_002661.5 splice_region, intron

Scores

Splicing: ADA: 0.00003152

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0130

Publications

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

PLCG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 16-81912723-G-A is Benign according to our data. Variant chr16-81912723-G-A is described in ClinVar as Benign. ClinVar VariationId is 472894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0284 (4334/152368) while in subpopulation NFE AF = 0.0434 (2953/68034). AF 95% confidence interval is 0.0421. There are 92 homozygotes in GnomAd4. There are 1942 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 4334 AD gene.

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	Effect	Exon Rank	Protein	UniProt
PLCG2	NM_002661.5	MANE Select	c.2054+7G>A	splice_region intron	N/A	NP_002652.2	P16885
PLCG2	NM_001425749.1		c.2054+7G>A	splice_region intron	N/A	NP_001412678.1	P16885
PLCG2	NM_001425750.1		c.2054+7G>A	splice_region intron	N/A	NP_001412679.1	P16885

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.2054+7G>A	splice_region intron	N/A	ENSP00000482457.1	P16885
PLCG2	ENST00000567980.5	TSL:1	n.2298+7G>A	splice_region intron	N/A
PLCG2	ENST00000902427.1		c.2207+7G>A	splice_region intron	N/A	ENSP00000572486.1

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

4336

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00911

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0346

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.0102

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0434

Gnomad OTH

AF:

0.0445

GnomAD2 exomes

AF:

0.0273

AC:

6111

AN:

223992

AF XY:

0.0282

show subpopulations

Gnomad AFR exome

AF:

0.00892

Gnomad AMR exome

AF:

0.0213

Gnomad ASJ exome

AF:

0.0446

Gnomad EAS exome

AF:

0.0000578

Gnomad FIN exome

AF:

0.0121

Gnomad NFE exome

AF:

0.0418

Gnomad OTH exome

AF:

0.0343

GnomAD4 exome

AF:

0.0407

AC:

58666

AN:

1440134

Hom.:

1390

Cov.:

AF XY:

0.0398

AC XY:

28469

AN XY:

714648

show subpopulations

African (AFR)

AF:

0.00719

AC:

237

AN:

32940

American (AMR)

AF:

0.0225

AC:

952

AN:

42398

Ashkenazi Jewish (ASJ)

AF:

0.0476

AC:

1156

AN:

24266

East Asian (EAS)

AF:

0.0000509

AC:

AN:

39262

South Asian (SAS)

AF:

0.0108

AC:

888

AN:

82196

European-Finnish (FIN)

AF:

0.0126

AC:

655

AN:

52136

Middle Eastern (MID)

AF:

0.0244

AC:

138

AN:

5656

European-Non Finnish (NFE)

AF:

0.0476

AC:

52454

AN:

1101774

Other (OTH)

AF:

0.0367

AC:

2184

AN:

59506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2759

5519

8278

11038

13797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2000

4000

6000

8000

10000

<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:

0.0284

AC:

4334

AN:

152368

Hom.:

Cov.:

AF XY:

0.0261

AC XY:

1942

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00909

AC:

378

AN:

41602

American (AMR)

AF:

0.0346

AC:

529

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

160

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00890

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0102

AC:

108

AN:

10626

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0434

AC:

2953

AN:

68034

Other (OTH)

AF:

0.0440

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

221

442

662

883

1104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0319

Hom.:

Bravo

AF:

0.0295

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Familial cold autoinflammatory syndrome 3 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.091

(source)

DANN

Benign

0.41

PhyloP100

-0.013

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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