rs10514519

Variant names:

• chr16-81941460-G-A
• rs10514519
• NM_002661.5:c.3481+1401G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002661.5(PLCG2):​c.3481+1401G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 152,054 control chromosomes in the GnomAD database, including 4,364 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4364 hom., cov: 32)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.3481+1401G>A		intron_variant	Intron 30 of 32	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.3481+1401G>A		intron_variant	Intron 31 of 33		NP_001412678.1
PLCG2	NM_001425750.1	c.3481+1401G>A		intron_variant	Intron 30 of 32		NP_001412679.1
PLCG2	NM_001425751.1	c.3481+1401G>A		intron_variant	Intron 31 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.3481+1401G>A		intron_variant	Intron 30 of 32	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33184 AN: 151936 Hom.: 4364 Cov.: 32

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0629

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.218 AC: 33200 AN: 152054 Hom.: 4364 Cov.: 32 AF XY: 0.213 AC XY: 15805 AN XY: 74324

African (AFR) AF: 0.377 AC: 15643 AN: 41440

American (AMR) AF: 0.129 AC: 1977 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3472

East Asian (EAS) AF: 0.0625 AC: 323 AN: 5168

South Asian (SAS) AF: 0.107 AC: 514 AN: 4824

European-Finnish (FIN) AF: 0.140 AC: 1475 AN: 10572

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12130 AN: 67968

Other (OTH) AF: 0.193 AC: 407 AN: 2110

Alfa AF: 0.188 Hom.: 9730

Bravo AF: 0.225

Asia WGS AF: 0.0960 AC: 338 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.92
DANN	Benign	0.20
PhyloP100		-0.17
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: rs10514519; hg19: chr16-81975065;