chr16-81912673-A-G

Position:

• chr16-81912673-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000564138.6(PLCG2):​c.2011A>G​(p.Ile671Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,612,688 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I671I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (65 hom.)
• Consequence: PLCG2 ENST00000564138.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.14

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014680892).
• BP6: Variant 16-81912673-A-G is Benign according to our data. Variant chr16-81912673-A-G is described in ClinVar as [Benign]. Clinvar id is 440160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81912673-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00228 (347/152338) while in subpopulation SAS AF= 0.0228 (110/4820). AF 95% confidence interval is 0.0194. There are 1 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 347 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.2011A>G	p.Ile671Val	missense_variant	19/33	ENST00000564138.6	NP_002652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.2011A>G	p.Ile671Val	missense_variant	19/33	1	NM_002661.5	ENSP00000482457	P1

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 347 AN: 152220 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00545 AC: 1338 AN: 245280 Hom.: 15 AF XY: 0.00667 AC XY: 887 AN XY: 133062

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.00155

Gnomad ASJ exome AF: 0.00912

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.0251

Gnomad FIN exome AF: 0.000523

Gnomad NFE exome AF: 0.00347

Gnomad OTH exome AF: 0.00677

GnomAD4 exome AF: 0.00361 AC: 5265 AN: 1460350 Hom.: 65 Cov.: 31 AF XY: 0.00428 AC XY: 3107 AN XY: 726350

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00209

Gnomad4 ASJ exome AF: 0.00904

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0249

Gnomad4 FIN exome AF: 0.00113

Gnomad4 NFE exome AF: 0.00207

Gnomad4 OTH exome AF: 0.00489

GnomAD4 genome AF: 0.00228 AC: 347 AN: 152338 Hom.: 1 Cov.: 33 AF XY: 0.00258 AC XY: 192 AN XY: 74486

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00342 Hom.: 4

Bravo AF: 0.00194

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000735 AC: 3

ESP6500EA AF: 0.00238 AC: 20

ExAC AF: 0.00566 AC: 685

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 28, 2023

- -

Familial cold autoinflammatory syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.45
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.83	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.39	.;N
REVEL	Uncertain	0.31
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.27
MVP		0.46
MPC		0.23
ClinPred		0.0068	T
GERP RS		4.0
Varity_R		0.094
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs150833842; hg19: chr16-81946278; COSMIC: COSV99080857;