chr16-81908398-C-T

Variant names:

• chr16-81908398-C-T
• rs113312523
• NM_002661.5:c.1558-18C>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.1558-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,609,916 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (55 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (44 hom.)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.326

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=-0.8).
• BP6: Variant 16-81908398-C-T is Benign according to our data. Variant chr16-81908398-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81908398-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (2038/152250) while in subpopulation AFR AF= 0.046 (1913/41542). AF 95% confidence interval is 0.0443. There are 55 homozygotes in gnomad4. There are 969 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2038 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.1558-18C>T		intron_variant	Intron 16 of 32	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.1558-18C>T		intron_variant	Intron 17 of 33		NP_001412678.1
PLCG2	NM_001425750.1	c.1558-18C>T		intron_variant	Intron 16 of 32		NP_001412679.1
PLCG2	NM_001425751.1	c.1558-18C>T		intron_variant	Intron 17 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.1558-18C>T		intron_variant	Intron 16 of 32	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2032 AN: 152132 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00329 AC: 811 AN: 246390 Hom.: 17 AF XY: 0.00239 AC XY: 319 AN XY: 133564

Gnomad AFR exome AF: 0.0452

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.0000537

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.00146 AC: 2133 AN: 1457666 Hom.: 44 Cov.: 30 AF XY: 0.00126 AC XY: 913 AN XY: 724970

Gnomad4 AFR exome AF: 0.0506

Gnomad4 AMR exome AF: 0.00297

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000233

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000514

Gnomad4 OTH exome AF: 0.00360

GnomAD4 genome AF: 0.0134 AC: 2038 AN: 152250 Hom.: 55 Cov.: 32 AF XY: 0.0130 AC XY: 969 AN XY: 74436

Gnomad4 AFR AF: 0.0460

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00609 Hom.: 4

Bravo AF: 0.0154

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cold autoinflammatory syndrome 3;C3553961:Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation Benign:1

Aug 31, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.80
CADD	Benign	7.6
DANN	Benign	0.58

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: rs113312523; hg19: chr16-81942003;