chr16-81786071-A-T

Variant names:

• chr16-81786071-A-T
• rs61749044
• NM_002661.5:c.82A>T

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.82A>T​(p.Met28Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,614,186 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.015 (218 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 8.94
• Publications: 26 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 (MetaRNN=0.0093021095).
• BP6: Variant 16-81786071-A-T is Benign according to our data. Variant chr16-81786071-A-T is described in ClinVar as Benign. ClinVar VariationId is 440153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.01 (1525/152338) while in subpopulation SAS AF = 0.017 (82/4826). AF 95% confidence interval is 0.015. There are 16 homozygotes in GnomAd4. There are 728 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1525 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.82A>T	p.Met28Leu	missense	Exon 2 of 33	NP_002652.2	P16885
	PLCG2	NM_001425749.1		c.82A>T	p.Met28Leu	missense	Exon 3 of 34	NP_001412678.1	P16885
	PLCG2	NM_001425750.1		c.82A>T	p.Met28Leu	missense	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.82A>T	p.Met28Leu	missense	Exon 2 of 33	ENSP00000482457.1	P16885
	PLCG2	ENST00000567980.5	TSL:1	n.326A>T		non_coding_transcript_exon	Exon 1 of 20
	PLCG2	ENST00000902427.1		c.82A>T	p.Met28Leu	missense	Exon 2 of 34	ENSP00000572486.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1525 AN: 152220 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.0108 AC: 2693 AN: 249582 AF XY: 0.0117

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00426

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00635

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.00825

GnomAD4 exome AF: 0.0153 AC: 22358 AN: 1461848 Hom.: 218 Cov.: 31 AF XY: 0.0152 AC XY: 11080 AN XY: 727228

African (AFR) AF: 0.00191 AC: 64 AN: 33480

American (AMR) AF: 0.00436 AC: 195 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26136

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

South Asian (SAS) AF: 0.0207 AC: 1782 AN: 86258

European-Finnish (FIN) AF: 0.00610 AC: 326 AN: 53420

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5766

European-Non Finnish (NFE) AF: 0.0172 AC: 19181 AN: 1111968

Other (OTH) AF: 0.0112 AC: 676 AN: 60396

GnomAD4 genome AF: 0.0100 AC: 1525 AN: 152338 Hom.: 16 Cov.: 32 AF XY: 0.00977 AC XY: 728 AN XY: 74500

African (AFR) AF: 0.00279 AC: 116 AN: 41588

American (AMR) AF: 0.00981 AC: 150 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4826

European-Finnish (FIN) AF: 0.00772 AC: 82 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0158 AC: 1075 AN: 68028

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.0132 Hom.: 5

Bravo AF: 0.00918

TwinsUK AF: 0.0210 AC: 78

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00445 AC: 18

ESP6500EA AF: 0.0132 AC: 110

ExAC AF: 0.0111 AC: 1344

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0159

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Familial cold autoinflammatory syndrome 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L
PhyloP100		8.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.25
Sift	Benign	0.33	T
Sift4G	Benign	0.29	T
Polyphen		0.85	P
Vest4		0.38
MutPred		0.53		Loss of sheet (P = 0.0357)
MPC		0.37
ClinPred		0.030	T
GERP RS		5.1
Varity_R		0.32
gMVP		0.66
Mutation Taster		=89/11	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: rs61749044; hg19: chr16-81819676;