rs200506549

Positions:

chr16-81893709-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

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 frequency of 0.00128 in 1,607,178 control chromosomes in the GnomAD database, including 5 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 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: 0.0009256

Clinical Significance

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

Conservation

PhyloP100: 1.11

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 16-81893709-G-A is Benign according to our data. Variant chr16-81893709-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 472908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81893709-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.11 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00162 (246/152264) while in subpopulation AMR AF= 0.00353 (54/15296). AF 95% confidence interval is 0.00278. There are 1 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 246 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.987G>A	p.Thr329Thr	splice_region_variant, synonymous_variant	12/33	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.987G>A	p.Thr329Thr	splice_region_variant, synonymous_variant	13/34		NP_001412678.1
PLCG2	NM_001425750.1 link	c.987G>A	p.Thr329Thr	splice_region_variant, synonymous_variant	12/33		NP_001412679.1
PLCG2	NM_001425751.1 link	c.987G>A	p.Thr329Thr	splice_region_variant, synonymous_variant	13/34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.987G>A	p.Thr329Thr	splice_region_variant, synonymous_variant	12/33	1	NM_002661.5	ENSP00000482457.1		P16885

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

GnomAD3 exomes

AF:

0.00129

AC:

320

AN:

247740

Hom.:

AF XY:

0.00143

AC XY:

193

AN XY:

134602

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 SAS exome

AF:

0.000492

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

Gnomad4 AFR exome

AF:

0.000330

Gnomad4 AMR exome

AF:

0.00134

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000349

Gnomad4 FIN exome

AF:

0.0000577

Gnomad4 NFE exome

AF:

0.00136

Gnomad4 OTH exome

AF:

0.00138

GnomAD4 genome

AF:

0.00162

AC:

246

AN:

152264

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00181

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.0101

Hom.:

835

Bravo

AF:

0.00180

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00344

EpiControl

AF:

0.00220

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	PLCG2: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.68

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

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