Genetic Variant NM_002661.5:c.565-10A>G (chr16-81870842-A-G) – 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.565-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 1,522,626 control chromosomes in the GnomAD database, including 1,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 77 hom., cov: 33)

Exomes 𝑓: 0.039 ( 1218 hom. )

Consequence

PLCG2
NM_002661.5 intron

Scores

Splicing: ADA: 0.000008560

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.32

Publications

2 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=-0.86).

BP6

Variant 16-81870842-A-G is Benign according to our data. Variant chr16-81870842-A-G is described in ClinVar as Benign. ClinVar VariationId is 472902.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 = 0.029 (4411/152256) while in subpopulation NFE AF = 0.0454 (3089/68018). AF 95% confidence interval is 0.0441. There are 77 homozygotes in GnomAd4. There are 2091 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 4411 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.565-10A>G	intron	N/A	NP_002652.2	P16885
PLCG2	NM_001425749.1		c.565-10A>G	intron	N/A	NP_001412678.1	P16885
PLCG2	NM_001425750.1		c.565-10A>G	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.565-10A>G	intron	N/A	ENSP00000482457.1	P16885
PLCG2	ENST00000567980.5	TSL:1	n.809-10A>G	intron	N/A
PLCG2	ENST00000902427.1		c.565-10A>G	intron	N/A	ENSP00000572486.1

Frequencies

GnomAD3 genomes

AF:

0.0290

AC:

4414

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00731

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0186

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.0457

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0454

Gnomad OTH

AF:

0.0316

GnomAD2 exomes

AF:

0.0335

AC:

7008

AN:

209084

AF XY:

0.0333

show subpopulations

Gnomad AFR exome

AF:

0.00737

Gnomad AMR exome

AF:

0.0160

Gnomad ASJ exome

AF:

0.0259

Gnomad EAS exome

AF:

0.0000702

Gnomad FIN exome

AF:

0.0549

Gnomad NFE exome

AF:

0.0473

Gnomad OTH exome

AF:

0.0299

GnomAD4 exome

AF:

0.0390

AC:

53424

AN:

1370370

Hom.:

1218

Cov.:

AF XY:

0.0381

AC XY:

26049

AN XY:

684000

show subpopulations

African (AFR)

AF:

0.00601

AC:

186

AN:

30954

American (AMR)

AF:

0.0165

AC:

629

AN:

38142

Ashkenazi Jewish (ASJ)

AF:

0.0232

AC:

577

AN:

24892

East Asian (EAS)

AF:

0.000130

AC:

AN:

38578

South Asian (SAS)

AF:

0.0131

AC:

1046

AN:

79660

European-Finnish (FIN)

AF:

0.0469

AC:

2458

AN:

52436

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

5502

European-Non Finnish (NFE)

AF:

0.0446

AC:

46506

AN:

1043164

Other (OTH)

AF:

0.0337

AC:

1923

AN:

57042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

2222

4443

6665

8886

11108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1696

3392

5088

6784

8480

<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:

0.0290

AC:

4411

AN:

152256

Hom.:

Cov.:

AF XY:

0.0281

AC XY:

2091

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00729

AC:

303

AN:

41568

American (AMR)

AF:

0.0186

AC:

284

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0137

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0457

AC:

484

AN:

10590

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0454

AC:

3089

AN:

68018

Other (OTH)

AF:

0.0313

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

224

447

671

894

1118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0252

Hom.:

Bravo

AF:

0.0262

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Familial cold autoinflammatory syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.19

(source)

DANN

Benign

0.62

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000086

dbscSNV1_RF

Benign

0.0

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