rs1143688

Variant names:

• chr16-81895883-C-T
• rs1143688
• NM_002661.5:c.1149C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-81895883-C-T
• chr16-81895883-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002661.5(PLCG2):​c.1149C>T​(p.Asp383Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,613,436 control chromosomes in the GnomAD database, including 124,140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10718 hom., cov: 31)
  • Exomes 𝑓: 0.38 (113422 hom.)
• Consequence: PLCG2 NM_002661.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.31
• Publications: 23 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• familial cold autoinflammatory syndrome 3

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 16-81895883-C-T is Benign according to our data. Variant chr16-81895883-C-T is described in ClinVar as Benign. ClinVar VariationId is 403320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	NM_002661.5	MANE Select	c.1149C>T	p.Asp383Asp	synonymous	Exon 13 of 33	NP_002652.2	P16885
	PLCG2	NM_001425749.1		c.1149C>T	p.Asp383Asp	synonymous	Exon 14 of 34	NP_001412678.1	P16885
	PLCG2	NM_001425750.1		c.1149C>T	p.Asp383Asp	synonymous	Exon 13 of 33	NP_001412679.1	P16885

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.1149C>T	p.Asp383Asp	synonymous	Exon 13 of 33	ENSP00000482457.1	P16885
	PLCG2	ENST00000567980.5	TSL:1	n.1393C>T		non_coding_transcript_exon	Exon 12 of 20
	PLCG2	ENST00000902427.1		c.1149C>T	p.Asp383Asp	synonymous	Exon 13 of 34	ENSP00000572486.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52187 AN: 151818 Hom.: 10711 Cov.: 31

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.429 AC: 107092 AN: 249514 AF XY: 0.422

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.659

Gnomad ASJ exome AF: 0.344

Gnomad EAS exome AF: 0.709

Gnomad FIN exome AF: 0.429

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.416

GnomAD4 exome AF: 0.384 AC: 560548 AN: 1461500 Hom.: 113422 Cov.: 43 AF XY: 0.383 AC XY: 278242 AN XY: 727078

African (AFR) AF: 0.131 AC: 4385 AN: 33480

American (AMR) AF: 0.641 AC: 28689 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 8941 AN: 26130

East Asian (EAS) AF: 0.702 AC: 27854 AN: 39694

South Asian (SAS) AF: 0.385 AC: 33172 AN: 86246

European-Finnish (FIN) AF: 0.434 AC: 23179 AN: 53402

Middle Eastern (MID) AF: 0.350 AC: 2020 AN: 5764

European-Non Finnish (NFE) AF: 0.368 AC: 409224 AN: 1111674

Other (OTH) AF: 0.382 AC: 23084 AN: 60388

GnomAD4 genome AF: 0.344 AC: 52202 AN: 151936 Hom.: 10718 Cov.: 31 AF XY: 0.356 AC XY: 26401 AN XY: 74242

African (AFR) AF: 0.145 AC: 5997 AN: 41476

American (AMR) AF: 0.531 AC: 8108 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1208 AN: 3468

East Asian (EAS) AF: 0.720 AC: 3694 AN: 5132

South Asian (SAS) AF: 0.399 AC: 1921 AN: 4816

European-Finnish (FIN) AF: 0.443 AC: 4675 AN: 10542

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.374 AC: 25393 AN: 67920

Other (OTH) AF: 0.376 AC: 795 AN: 2112

Alfa AF: 0.347 Hom.: 4932

Bravo AF: 0.342

Asia WGS AF: 0.534 AC: 1855 AN: 3478

EpiCase AF: 0.364

EpiControl AF: 0.368

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Familial cold autoinflammatory syndrome 3 (2)
-	-	1	Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.49
DANN	Benign	0.92
PhyloP100		-1.3
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: rs1143688; hg19: chr16-81929488; COSMIC: COSV108182757;