rs1143685

Variant names:

• chr16-81786163-T-C
• rs1143685
• NM_002661.5:c.174T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-81786163-T-C
• chr16-81786163-T-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.174T>C​(p.Ala58Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,613,708 control chromosomes in the GnomAD database, including 394,472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36283 hom., cov: 33)
  • Exomes 𝑓: 0.70 (358189 hom.)
• Consequence: PLCG2 NM_002661.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -3.07
• Publications: 17 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=-0.66).
• BP6: Variant 16-81786163-T-C is Benign according to our data. Variant chr16-81786163-T-C is described in ClinVar as Benign. ClinVar VariationId is 403316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.853 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.174T>C	p.Ala58Ala	synonymous	Exon 2 of 33	NP_002652.2	P16885
	PLCG2	NM_001425749.1		c.174T>C	p.Ala58Ala	synonymous	Exon 3 of 34	NP_001412678.1	P16885
	PLCG2	NM_001425750.1		c.174T>C	p.Ala58Ala	synonymous	Exon 2 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.174T>C	p.Ala58Ala	synonymous	Exon 2 of 33	ENSP00000482457.1	P16885
	PLCG2	ENST00000567980.5	TSL:1	n.418T>C		non_coding_transcript_exon	Exon 1 of 20
	PLCG2	ENST00000902427.1		c.174T>C	p.Ala58Ala	synonymous	Exon 2 of 34	ENSP00000572486.1

Frequencies

GnomAD3 genomes AF: 0.689 AC: 104674 AN: 152006 Hom.: 36262 Cov.: 33

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.730

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.768

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.668

GnomAD2 exomes AF: 0.727 AC: 180856 AN: 248772 AF XY: 0.727

Gnomad AFR exome AF: 0.641

Gnomad AMR exome AF: 0.779

Gnomad ASJ exome AF: 0.684

Gnomad EAS exome AF: 0.876

Gnomad FIN exome AF: 0.752

Gnomad NFE exome AF: 0.689

Gnomad OTH exome AF: 0.703

GnomAD4 exome AF: 0.699 AC: 1020982 AN: 1461586 Hom.: 358189 Cov.: 51 AF XY: 0.700 AC XY: 509115 AN XY: 727082

African (AFR) AF: 0.643 AC: 21536 AN: 33476

American (AMR) AF: 0.774 AC: 34584 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 17732 AN: 26134

East Asian (EAS) AF: 0.891 AC: 35361 AN: 39700

South Asian (SAS) AF: 0.768 AC: 66261 AN: 86238

European-Finnish (FIN) AF: 0.744 AC: 39712 AN: 53400

Middle Eastern (MID) AF: 0.710 AC: 4069 AN: 5730

European-Non Finnish (NFE) AF: 0.683 AC: 759881 AN: 1111828

Other (OTH) AF: 0.693 AC: 41846 AN: 60376

GnomAD4 genome AF: 0.689 AC: 104736 AN: 152122 Hom.: 36283 Cov.: 33 AF XY: 0.696 AC XY: 51787 AN XY: 74356

African (AFR) AF: 0.643 AC: 26698 AN: 41490

American (AMR) AF: 0.730 AC: 11165 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2324 AN: 3472

East Asian (EAS) AF: 0.874 AC: 4516 AN: 5168

South Asian (SAS) AF: 0.768 AC: 3697 AN: 4814

European-Finnish (FIN) AF: 0.748 AC: 7918 AN: 10582

Middle Eastern (MID) AF: 0.695 AC: 203 AN: 292

European-Non Finnish (NFE) AF: 0.682 AC: 46339 AN: 67986

Other (OTH) AF: 0.665 AC: 1408 AN: 2116

Alfa AF: 0.686 Hom.: 53264

Bravo AF: 0.686

Asia WGS AF: 0.747 AC: 2598 AN: 3478

EpiCase AF: 0.683

EpiControl AF: 0.683

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.25
DANN	Benign	0.76
PhyloP100		-3.1
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: rs1143685; hg19: chr16-81819768; COSMIC: COSV108182756;