rs4888183

Variant names:

• chr16-81859103-T-A
• rs4888183
• NM_002661.5:c.432-13T>A

Your query was ambiguous. Multiple possible variants found:

• chr16-81859103-T-A
• chr16-81859103-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002661.5(PLCG2):​c.432-13T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 1,517,952 control chromosomes in the GnomAD database, including 228,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23448 hom., cov: 33)
  • Exomes 𝑓: 0.55 (205146 hom.)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0710
• Publications: 13 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-81859103-T-A is Benign according to our data. Variant chr16-81859103-T-A is described in ClinVar as Benign. ClinVar VariationId is 403318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	NM_002661.5	MANE Select	c.432-13T>A		intron	N/A	NP_002652.2
	PLCG2	NM_001425749.1		c.432-13T>A		intron	N/A	NP_001412678.1
	PLCG2	NM_001425750.1		c.432-13T>A		intron	N/A	NP_001412679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.432-13T>A		intron	N/A	ENSP00000482457.1
	PLCG2	ENST00000567980.5	TSL:1	n.676-13T>A		intron	N/A
	PLCG2	ENST00000565054.7	TSL:5	c.432-13T>A		intron	N/A	ENSP00000520638.1

Frequencies

GnomAD3 genomes AF: 0.553 AC: 84062 AN: 152026 Hom.: 23445 Cov.: 33

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.569

GnomAD2 exomes AF: 0.554 AC: 137831 AN: 248668 AF XY: 0.549

Gnomad AFR exome AF: 0.526

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.604

Gnomad EAS exome AF: 0.635

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.559

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.546 AC: 745245 AN: 1365808 Hom.: 205146 Cov.: 22 AF XY: 0.544 AC XY: 372498 AN XY: 685244

African (AFR) AF: 0.519 AC: 16439 AN: 31674

American (AMR) AF: 0.557 AC: 24780 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 15429 AN: 25542

East Asian (EAS) AF: 0.577 AC: 22643 AN: 39240

South Asian (SAS) AF: 0.454 AC: 38251 AN: 84304

European-Finnish (FIN) AF: 0.605 AC: 32255 AN: 53294

Middle Eastern (MID) AF: 0.635 AC: 3543 AN: 5582

European-Non Finnish (NFE) AF: 0.547 AC: 559981 AN: 1024576

Other (OTH) AF: 0.559 AC: 31924 AN: 57070

GnomAD4 genome AF: 0.553 AC: 84106 AN: 152144 Hom.: 23448 Cov.: 33 AF XY: 0.554 AC XY: 41185 AN XY: 74366

African (AFR) AF: 0.521 AC: 21630 AN: 41478

American (AMR) AF: 0.583 AC: 8917 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2033 AN: 3470

East Asian (EAS) AF: 0.610 AC: 3167 AN: 5188

South Asian (SAS) AF: 0.447 AC: 2154 AN: 4824

European-Finnish (FIN) AF: 0.609 AC: 6438 AN: 10576

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37770 AN: 68000

Other (OTH) AF: 0.567 AC: 1198 AN: 2112

Alfa AF: 0.559 Hom.: 4316

Bravo AF: 0.552

Asia WGS AF: 0.512 AC: 1779 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Familial cold autoinflammatory syndrome 3 (2)
-	-	1	Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.1
DANN	Benign	0.73
PhyloP100		-0.071
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4888183; hg19: chr16-81892708; COSMIC: COSV63878556;