16-81889176-A-T

Position:

chr16-81889176-A-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. H257H) has been classified as Likely benign.

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

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 links:

PLCG2 (HGNC:):

PLCG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 440155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81889176-A-T is described in Lovd as [Likely_benign]. Variant chr16-81889176-A-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4074 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCG2	NM_002661.5 linkuse as main transcript	c.770A>T	p.His257Leu	missense_variant	10/33	ENST00000564138.6	NP_002652.2	P16885

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 linkuse as main transcript	c.770A>T	p.His257Leu	missense_variant	10/33	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

GnomAD3 exomes

AF:

0.0264

AC:

6225

AN:

236222

Hom.:

128

AF XY:

0.0263

AC XY:

3354

AN XY:

127694

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 SAS exome

AF:

0.00418

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

Gnomad4 AFR exome

AF:

0.00534

Gnomad4 AMR exome

AF:

0.0183

Gnomad4 ASJ exome

AF:

0.0267

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.00422

Gnomad4 FIN exome

AF:

0.0396

Gnomad4 NFE exome

AF:

0.0409

Gnomad4 OTH exome

AF:

0.0313

GnomAD4 genome

AF:

0.0270

AC:

4074

AN:

150806

Hom.:

Cov.:

AF XY:

0.0262

AC XY:

1926

AN XY:

73558

show subpopulations

Gnomad4 AFR

AF:

0.00677

Gnomad4 AMR

AF:

0.0358

Gnomad4 ASJ

AF:

0.0298

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00325

Gnomad4 FIN

AF:

0.0326

Gnomad4 NFE

AF:

0.0397

Gnomad4 OTH

AF:

0.0321

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

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

- -

Familial cold autoinflammatory syndrome 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over