rs61749044

chr16-81786071-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002661.5(PLCG2):c.82A>T(p.Met28Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,614,186 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.015 (218 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 8.94

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0093021095).
• BP6: Variant 16-81786071-A-T is Benign according to our data. Variant chr16-81786071-A-T is described in ClinVar as [Benign]. Clinvar id is 440153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81786071-A-T is described in Lovd as [Likely_benign]. Variant chr16-81786071-A-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.01 (1525/152338) while in subpopulation SAS AF= 0.017 (82/4826). AF 95% confidence interval is 0.015. There are 16 homozygotes in gnomad4. There are 728 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1525 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5	c.82A>T	p.Met28Leu	missense_variant	2/33	ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6	c.82A>T	p.Met28Leu	missense_variant	2/33	1	NM_002661.5	P1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1525 AN: 152220 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.0108 AC: 2693 AN: 249582 Hom.: 20 AF XY: 0.0117 AC XY: 1590 AN XY: 135404

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00426

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0209

Gnomad FIN exome AF: 0.00635

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.00825

GnomAD4 exome AF: 0.0153 AC: 22358 AN: 1461848 Hom.: 218 Cov.: 31 AF XY: 0.0152 AC XY: 11080 AN XY: 727228

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0207

Gnomad4 FIN exome AF: 0.00610

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0100 AC: 1525 AN: 152338 Hom.: 16 Cov.: 32 AF XY: 0.00977 AC XY: 728 AN XY: 74500

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.00772

Gnomad4 NFE AF: 0.0158

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.0132 Hom.: 5

Bravo AF: 0.00918

TwinsUK AF: 0.0210 AC: 78

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00445 AC: 18

ESP6500EA AF: 0.0132 AC: 110

ExAC AF: 0.0111 AC: 1344

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0159

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PLCG2: BS1, BS2 -

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Uncertain	0.97
DEOGEN2	Benign	0.26	T;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.0093	T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.82	N;.;N
Sift	Benign	0.33	T;.;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.85	.;P;.
Vest4		0.38, 0.24
MutPred		0.53		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MPC		0.37
ClinPred		0.030	T
GERP RS		5.1
Varity_R		0.32
gMVP		0.66

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

Other links and lift over

dbSNP: rs61749044; hg19: chr16-81819676;