rs138158454

chr16-81912723-G-Achr16-81912723-G-T

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.2054+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,592,502 control chromosomes in the GnomAD database, including 1,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (92 hom., cov: 33)
  • Exomes 𝑓: 0.041 (1390 hom.)
• Consequence: PLCG2 NM_002661.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003152
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0130

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=-0.82).
• BP6: Variant 16-81912723-G-A is Benign according to our data. Variant chr16-81912723-G-A is described in ClinVar as [Benign]. Clinvar id is 472894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81912723-G-A is described in Lovd as [Benign]. Variant chr16-81912723-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0284 (4334/152368) while in subpopulation NFE AF= 0.0434 (2953/68034). AF 95% confidence interval is 0.0421. There are 92 homozygotes in gnomad4. There are 1942 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 4336 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5	c.2054+7G>A		splice_region_variant, intron_variant		ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6	c.2054+7G>A		splice_region_variant, intron_variant		1	NM_002661.5	P1

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4336 AN: 152250 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.00911

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0346

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0445

GnomAD3 exomes AF: 0.0273 AC: 6111 AN: 223992 Hom.: 123 AF XY: 0.0282 AC XY: 3399 AN XY: 120634

Gnomad AFR exome AF: 0.00892

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0446

Gnomad EAS exome AF: 0.0000578

Gnomad SAS exome AF: 0.0109

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0418

Gnomad OTH exome AF: 0.0343

GnomAD4 exome AF: 0.0407 AC: 58666 AN: 1440134 Hom.: 1390 Cov.: 31 AF XY: 0.0398 AC XY: 28469 AN XY: 714648

Gnomad4 AFR exome AF: 0.00719

Gnomad4 AMR exome AF: 0.0225

Gnomad4 ASJ exome AF: 0.0476

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0126

Gnomad4 NFE exome AF: 0.0476

Gnomad4 OTH exome AF: 0.0367

GnomAD4 genome AF: 0.0284 AC: 4334 AN: 152368 Hom.: 92 Cov.: 33 AF XY: 0.0261 AC XY: 1942 AN XY: 74500

Gnomad4 AFR AF: 0.00909

Gnomad4 AMR AF: 0.0346

Gnomad4 ASJ AF: 0.0461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00890

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.0434

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0315 Hom.: 39

Bravo AF: 0.0295

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Familial cold autoinflammatory syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.091
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs138158454; hg19: chr16-81946328;