16-81889176-A-T

Variant names:

• chr16-81889176-A-T
• rs45443101
• NM_002661.5:c.770A>T
• PLCG2 p.His257Leu

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002661.5(PLCG2):​c.770A>T​(p.His257Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 1,584,662 control chromosomes in the GnomAD database, including 1,191 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H257R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.027 (85 hom., cov: 31)
  • Exomes 𝑓: 0.035 (1106 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.484
• 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, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• familial cold autoinflammatory syndrome 3

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003948629).
• BP6: Variant 16-81889176-A-T is Benign according to our data. Variant chr16-81889176-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 440155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.027 (4074/150806) while in subpopulation NFE AF = 0.0397 (2695/67824). AF 95% confidence interval is 0.0385. There are 85 homozygotes in GnomAd4. There are 1926 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4074 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	NM_002661.5	MANE Select	c.770A>T	p.His257Leu	missense	Exon 10 of 33	NP_002652.2	P16885
	PLCG2	NM_001425749.1		c.770A>T	p.His257Leu	missense	Exon 11 of 34	NP_001412678.1	P16885
	PLCG2	NM_001425750.1		c.770A>T	p.His257Leu	missense	Exon 10 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.770A>T	p.His257Leu	missense	Exon 10 of 33	ENSP00000482457.1	P16885
	PLCG2	ENST00000567980.5	TSL:1	n.1014A>T		non_coding_transcript_exon	Exon 9 of 20
	PLCG2	ENST00000902427.1		c.770A>T	p.His257Leu	missense	Exon 10 of 34	ENSP00000572486.1

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4075 AN: 150688 Hom.: 85 Cov.: 31

Gnomad AFR AF: 0.00679

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0359

Gnomad ASJ AF: 0.0298

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00325

Gnomad FIN AF: 0.0326

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0329

GnomAD2 exomes AF: 0.0264 AC: 6225 AN: 236222 AF XY: 0.0263

Gnomad AFR exome AF: 0.00642

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.0000568

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0392

Gnomad OTH exome AF: 0.0359

GnomAD4 exome AF: 0.0354 AC: 50710 AN: 1433856 Hom.: 1106 Cov.: 26 AF XY: 0.0344 AC XY: 24568 AN XY: 713648

African (AFR) AF: 0.00534 AC: 177 AN: 33124

American (AMR) AF: 0.0183 AC: 799 AN: 43624

Ashkenazi Jewish (ASJ) AF: 0.0267 AC: 687 AN: 25694

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39568

South Asian (SAS) AF: 0.00422 AC: 354 AN: 83920

European-Finnish (FIN) AF: 0.0396 AC: 2093 AN: 52884

Middle Eastern (MID) AF: 0.0217 AC: 124 AN: 5716

European-Non Finnish (NFE) AF: 0.0409 AC: 44609 AN: 1089866

Other (OTH) AF: 0.0313 AC: 1864 AN: 59460

GnomAD4 genome AF: 0.0270 AC: 4074 AN: 150806 Hom.: 85 Cov.: 31 AF XY: 0.0262 AC XY: 1926 AN XY: 73558

African (AFR) AF: 0.00677 AC: 278 AN: 41088

American (AMR) AF: 0.0358 AC: 537 AN: 14990

Ashkenazi Jewish (ASJ) AF: 0.0298 AC: 103 AN: 3462

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5080

South Asian (SAS) AF: 0.00325 AC: 15 AN: 4616

European-Finnish (FIN) AF: 0.0326 AC: 341 AN: 10454

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0397 AC: 2695 AN: 67824

Other (OTH) AF: 0.0321 AC: 67 AN: 2086

Alfa AF: 0.0324 Hom.: 74

Bravo AF: 0.0263

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.7
DANN	Benign	0.86
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.094	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.48
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.044
Sift	Benign	0.48	T
Sift4G	Benign	0.36	T
Varity_R		0.055
gMVP		0.28
Mutation Taster		=96/4	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs45443101;

hg19: chr16-81922781;

COSMIC: COSV63877404;

COSMIC: COSV63877404;