chr16-81870842-A-G

Variant names:

• chr16-81870842-A-G
• rs62046684
• NM_002661.5:c.565-10A>G

Variant summary

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

The NM_002661.5(PLCG2):​c.565-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 1,522,626 control chromosomes in the GnomAD database, including 1,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (77 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1218 hom.)
• Consequence: PLCG2 NM_002661.5 intron
• Scores: Splicing: ADA: 0.000008560
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.32

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 (BayesDel_noAF=-0.86).
• BP6: Variant 16-81870842-A-G is Benign according to our data. Variant chr16-81870842-A-G is described in ClinVar as [Benign]. Clinvar id is 472902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81870842-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.029 (4411/152256) while in subpopulation NFE AF= 0.0454 (3089/68018). AF 95% confidence interval is 0.0441. There are 77 homozygotes in gnomad4. There are 2091 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4411 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.565-10A>G		intron_variant	Intron 6 of 32	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.565-10A>G		intron_variant	Intron 7 of 33		NP_001412678.1
PLCG2	NM_001425750.1	c.565-10A>G		intron_variant	Intron 6 of 32		NP_001412679.1
PLCG2	NM_001425751.1	c.565-10A>G		intron_variant	Intron 7 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.565-10A>G		intron_variant	Intron 6 of 32	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4414 AN: 152138 Hom.: 77 Cov.: 33

Gnomad AFR AF: 0.00731

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0457

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0335 AC: 7008 AN: 209084 Hom.: 170 AF XY: 0.0333 AC XY: 3813 AN XY: 114418

Gnomad AFR exome AF: 0.00737

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0259

Gnomad EAS exome AF: 0.0000702

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.0549

Gnomad NFE exome AF: 0.0473

Gnomad OTH exome AF: 0.0299

GnomAD4 exome AF: 0.0390 AC: 53424 AN: 1370370 Hom.: 1218 Cov.: 20 AF XY: 0.0381 AC XY: 26049 AN XY: 684000

Gnomad4 AFR exome AF: 0.00601

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0232

Gnomad4 EAS exome AF: 0.000130

Gnomad4 SAS exome AF: 0.0131

Gnomad4 FIN exome AF: 0.0469

Gnomad4 NFE exome AF: 0.0446

Gnomad4 OTH exome AF: 0.0337

GnomAD4 genome AF: 0.0290 AC: 4411 AN: 152256 Hom.: 77 Cov.: 33 AF XY: 0.0281 AC XY: 2091 AN XY: 74426

Gnomad4 AFR AF: 0.00729

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.0457

Gnomad4 NFE AF: 0.0454

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0252 Hom.: 27

Bravo AF: 0.0262

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial cold autoinflammatory syndrome 3 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.19
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000086
dbscSNV1_RF	Benign	0.0
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: rs62046684; hg19: chr16-81904447;