NM_002661.5:c.1558-18C>T

Variant names:

• chr16-81908398-C-T
• rs113312523
• NM_002661.5:c.1558-18C>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.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
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• familial cold autoinflammatory syndrome 3

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 445753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2038 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.1558-18C>T		intron	N/A	NP_002652.2
	PLCG2	NM_001425749.1		c.1558-18C>T		intron	N/A	NP_001412678.1
	PLCG2	NM_001425750.1		c.1558-18C>T		intron	N/A	NP_001412679.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.1558-18C>T		intron	N/A	ENSP00000482457.1
	PLCG2	ENST00000567980.5	TSL:1	n.1802-18C>T		intron	N/A
	PLCG2	ENST00000902427.1		c.1711-18C>T		intron	N/A	ENSP00000572486.1

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

GnomAD2 exomes AF: 0.00329 AC: 811 AN: 246390 AF XY: 0.00239

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 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

African (AFR) AF: 0.0506 AC: 1691 AN: 33398

American (AMR) AF: 0.00297 AC: 132 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.000233 AC: 20 AN: 85666

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53258

Middle Eastern (MID) AF: 0.00262 AC: 15 AN: 5736

European-Non Finnish (NFE) AF: 0.0000514 AC: 57 AN: 1109374

Other (OTH) AF: 0.00360 AC: 217 AN: 60236

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

African (AFR) AF: 0.0460 AC: 1913 AN: 41542

American (AMR) AF: 0.00602 AC: 92 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68016

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00657 Hom.: 15

Bravo AF: 0.0154

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Familial cold autoinflammatory syndrome 3 (1)
-	-	1	Familial cold autoinflammatory syndrome 3;C3553961:Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.6
DANN	Benign	0.58
PhyloP100		-0.33
Mutation Taster		=100/0	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: rs113312523; hg19: chr16-81942003;