rs187956469

Variant names:

• chr16-81905484-T-C
• rs187956469
• NM_002661.5:c.1444T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002661.5(PLCG2):​c.1444T>C​(p.Tyr482His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,613,982 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y482Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (24 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 3.09
• Publications: 19 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008223802).
• BP6: Variant 16-81905484-T-C is Benign according to our data. Variant chr16-81905484-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 440158.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00336 (512/152326) while in subpopulation NFE AF = 0.00509 (346/68014). AF 95% confidence interval is 0.00465. There are 1 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 512 AD gene.

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.1444T>C	p.Tyr482His	missense	Exon 15 of 33	NP_002652.2
	PLCG2	NM_001425749.1		c.1444T>C	p.Tyr482His	missense	Exon 16 of 34	NP_001412678.1
	PLCG2	NM_001425750.1		c.1444T>C	p.Tyr482His	missense	Exon 15 of 33	NP_001412679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.1444T>C	p.Tyr482His	missense	Exon 15 of 33	ENSP00000482457.1
	PLCG2	ENST00000567980.5	TSL:1	n.1688T>C		non_coding_transcript_exon	Exon 14 of 20
	PLCG2	ENST00000565054.7	TSL:5	c.1444T>C	p.Tyr482His	missense	Exon 16 of 34	ENSP00000520638.1

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 512 AN: 152208 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00360 AC: 898 AN: 249386 AF XY: 0.00355

Gnomad AFR exome AF: 0.000841

Gnomad AMR exome AF: 0.00386

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000974

Gnomad NFE exome AF: 0.00476

Gnomad OTH exome AF: 0.00529

GnomAD4 exome AF: 0.00392 AC: 5737 AN: 1461656 Hom.: 24 Cov.: 30 AF XY: 0.00388 AC XY: 2824 AN XY: 727164

African (AFR) AF: 0.000777 AC: 26 AN: 33478

American (AMR) AF: 0.00380 AC: 170 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0146 AC: 381 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00107 AC: 92 AN: 86252

European-Finnish (FIN) AF: 0.00125 AC: 67 AN: 53418

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.00420 AC: 4669 AN: 1111806

Other (OTH) AF: 0.00489 AC: 295 AN: 60378

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152326 Hom.: 1 Cov.: 33 AF XY: 0.00297 AC XY: 221 AN XY: 74500

African (AFR) AF: 0.000890 AC: 37 AN: 41580

American (AMR) AF: 0.00392 AC: 60 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10630

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00509 AC: 346 AN: 68014

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00448 Hom.: 7

Bravo AF: 0.00362

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000488 AC: 2

ESP6500EA AF: 0.00489 AC: 41

ExAC AF: 0.00330 AC: 399

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00643

EpiControl AF: 0.00504

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	1	Familial cold autoinflammatory syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.00052
Eigen_PC	Benign	0.0084
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.13
Sift	Benign	0.056	T
Sift4G	Uncertain	0.059	T
Polyphen		0.97	D
Vest4		0.17
MVP		0.71
MPC		0.35
ClinPred		0.024	T
GERP RS		2.9
Varity_R		0.18
gMVP		0.49
Mutation Taster		=88/12	polymorphism

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: rs187956469; hg19: chr16-81939089;