16-81889176-A-T

Variant names:

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.770A>T(p.His257Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 1,584,662 control chromosomes in the GnomAD database, including 1,191 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H257R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.027 ( 85 hom., cov: 31)

Exomes 𝑓: 0.035 ( 1106 hom. )

Consequence

PLCG2
NM_002661.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.484

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003948629).

BP6

Variant 16-81889176-A-T is Benign according to our data. Variant chr16-81889176-A-T is described in ClinVar as Benign. ClinVar VariationId is 440155.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 = 0.027 (4074/150806) while in subpopulation NFE AF = 0.0397 (2695/67824). AF 95% confidence interval is 0.0385. There are 85 homozygotes in GnomAd4. There are 1926 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 4074 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.770A>T	p.His257Leu	missense_variant	Exon 10 of 33	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.770A>T	p.His257Leu	missense_variant	Exon 11 of 34		NP_001412678.1
PLCG2	NM_001425750.1 link	c.770A>T	p.His257Leu	missense_variant	Exon 10 of 33		NP_001412679.1
PLCG2	NM_001425751.1 link	c.770A>T	p.His257Leu	missense_variant	Exon 11 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.770A>T	p.His257Leu	missense_variant	Exon 10 of 33	1	NM_002661.5	ENSP00000482457.1		P16885

Frequencies

GnomAD3 genomes

AF:

0.0270

AC:

4075

AN:

150688

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00679

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0359

Gnomad ASJ

AF:

0.0298

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00325

Gnomad FIN

AF:

0.0326

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0397

Gnomad OTH

AF:

0.0329

GnomAD2 exomes

AF:

0.0264

AC:

6225

AN:

236222

AF XY:

0.0263

show subpopulations

Gnomad AFR exome

AF:

0.00642

Gnomad AMR exome

AF:

0.0180

Gnomad ASJ exome

AF:

0.0281

Gnomad EAS exome

AF:

0.0000568

Gnomad FIN exome

AF:

0.0366

Gnomad NFE exome

AF:

0.0392

Gnomad OTH exome

AF:

0.0359

GnomAD4 exome

AF:

0.0354

AC:

50710

AN:

1433856

Hom.:

1106

Cov.:

AF XY:

0.0344

AC XY:

24568

AN XY:

713648

show subpopulations

African (AFR)

AF:

0.00534

AC:

177

AN:

33124

American (AMR)

AF:

0.0183

AC:

799

AN:

43624

Ashkenazi Jewish (ASJ)

AF:

0.0267

AC:

687

AN:

25694

East Asian (EAS)

AF:

0.0000758

AC:

AN:

39568

South Asian (SAS)

AF:

0.00422

AC:

354

AN:

83920

European-Finnish (FIN)

AF:

0.0396

AC:

2093

AN:

52884

Middle Eastern (MID)

AF:

0.0217

AC:

124

AN:

5716

European-Non Finnish (NFE)

AF:

0.0409

AC:

44609

AN:

1089866

Other (OTH)

AF:

0.0313

AC:

1864

AN:

59460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1995

3990

5985

7980

9975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1622

3244

4866

6488

8110

<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:

0.0270

AC:

4074

AN:

150806

Hom.:

Cov.:

AF XY:

0.0262

AC XY:

1926

AN XY:

73558

show subpopulations

African (AFR)

AF:

0.00677

AC:

278

AN:

41088

American (AMR)

AF:

0.0358

AC:

537

AN:

14990

Ashkenazi Jewish (ASJ)

AF:

0.0298

AC:

103

AN:

3462

East Asian (EAS)

AF:

0.000197

AC:

AN:

5080

South Asian (SAS)

AF:

0.00325

AC:

AN:

4616

European-Finnish (FIN)

AF:

0.0326

AC:

341

AN:

10454

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0397

AC:

2695

AN:

67824

Other (OTH)

AF:

0.0321

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

194

388

581

775

969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0324

Hom.:

Bravo

AF:

0.0263

TwinsUK

AF:

0.0402

AC:

149

ALSPAC

AF:

0.0415

AC:

160

ESP6500AA

AF:

0.00971

AC:

ESP6500EA

AF:

0.0378

AC:

314

ExAC

AF:

0.0256

AC:

3099

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial cold autoinflammatory syndrome 3

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.58

CADD

Benign

2.7

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.26

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.094

T;T

MetaRNN

Benign

0.0039

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.6

N;.

PhyloP100

-0.48

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.26

.;N

REVEL

Benign

0.044

Sift

Benign

0.48

.;T

Sift4G

Benign

0.36

T;T

Polyphen

0.0

B;.

Vest4

0.080

MPC

0.077

ClinPred

0.000058

GERP RS

-3.8

Varity_R

0.055

gMVP

0.28

Mutation Taster

=96/4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over