16-81785881-C-G

Variant names:

• chr16-81785881-C-G
• rs4354929
• NM_002661.5:c.-47-62C>G

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.-47-62C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 1,010,280 control chromosomes in the GnomAD database, including 101,463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15688 hom., cov: 32)
  • Exomes 𝑓: 0.44 (85775 hom.)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.29
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-81785881-C-G is Benign according to our data. Variant chr16-81785881-C-G is described in ClinVar as Benign. ClinVar VariationId is 1266240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.622 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.-47-62C>G		intron	N/A	NP_002652.2	P16885
	PLCG2	NM_001425749.1		c.-47-62C>G		intron	N/A	NP_001412678.1	P16885
	PLCG2	NM_001425750.1		c.-47-62C>G		intron	N/A	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.-47-62C>G		intron	N/A	ENSP00000482457.1	P16885
	PLCG2	ENST00000567980.5	TSL:1	n.136C>G		non_coding_transcript_exon	Exon 1 of 20
	PLCG2	ENST00000902431.1		c.-109C>G		5_prime_UTR	Exon 1 of 32	ENSP00000572490.1

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68360 AN: 151906 Hom.: 15676 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.378

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.410

GnomAD4 exome AF: 0.441 AC: 378352 AN: 858256 Hom.: 85775 Cov.: 11 AF XY: 0.447 AC XY: 195811 AN XY: 437872

African (AFR) AF: 0.517 AC: 10719 AN: 20724

American (AMR) AF: 0.397 AC: 11679 AN: 29436

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 6438 AN: 17050

East Asian (EAS) AF: 0.337 AC: 12216 AN: 36202

South Asian (SAS) AF: 0.642 AC: 38655 AN: 60176

European-Finnish (FIN) AF: 0.460 AC: 21485 AN: 46744

Middle Eastern (MID) AF: 0.409 AC: 1774 AN: 4334

European-Non Finnish (NFE) AF: 0.428 AC: 258189 AN: 603900

Other (OTH) AF: 0.433 AC: 17197 AN: 39690

GnomAD4 genome AF: 0.450 AC: 68411 AN: 152024 Hom.: 15688 Cov.: 32 AF XY: 0.455 AC XY: 33820 AN XY: 74314

African (AFR) AF: 0.517 AC: 21402 AN: 41430

American (AMR) AF: 0.392 AC: 5995 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1334 AN: 3470

East Asian (EAS) AF: 0.293 AC: 1516 AN: 5174

South Asian (SAS) AF: 0.640 AC: 3087 AN: 4820

European-Finnish (FIN) AF: 0.458 AC: 4846 AN: 10570

Middle Eastern (MID) AF: 0.376 AC: 109 AN: 290

European-Non Finnish (NFE) AF: 0.427 AC: 29034 AN: 67956

Other (OTH) AF: 0.411 AC: 869 AN: 2114

Alfa AF: 0.447 Hom.: 1896

Bravo AF: 0.438

Asia WGS AF: 0.442 AC: 1536 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.053
DANN	Benign	0.61
PhyloP100		-3.3
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: rs4354929; hg19: chr16-81819486; COSMIC: COSV63875975; COSMIC: COSV63875975;