rs74032923

Variant names:

• chr16-81921224-C-T
• rs74032923
• NM_002661.5:c.2262C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-81921224-C-T
• chr16-81921224-C-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002661.5(PLCG2):​c.2262C>T​(p.Asp754Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,604,366 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (22 hom.)
• Consequence: PLCG2 NM_002661.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.29
• Publications: 6 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• familial cold autoinflammatory syndrome 3

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 16-81921224-C-T is Benign according to our data. Variant chr16-81921224-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 472897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00808 (1229/152110) while in subpopulation AFR AF = 0.0283 (1174/41474). AF 95% confidence interval is 0.027. There are 14 homozygotes in GnomAd4. There are 614 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1229 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.2262C>T	p.Asp754Asp	synonymous	Exon 21 of 33	NP_002652.2	P16885
	PLCG2	NM_001425749.1		c.2262C>T	p.Asp754Asp	synonymous	Exon 22 of 34	NP_001412678.1	P16885
	PLCG2	NM_001425750.1		c.2262C>T	p.Asp754Asp	synonymous	Exon 21 of 33	NP_001412679.1	P16885

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.2262C>T	p.Asp754Asp	synonymous	Exon 21 of 33	ENSP00000482457.1	P16885
	PLCG2	ENST00000567980.5	TSL:1	n.2506C>T		non_coding_transcript_exon	Exon 20 of 20
	PLCG2	ENST00000902427.1		c.2415C>T	p.Asp805Asp	synonymous	Exon 22 of 34	ENSP00000572486.1

Frequencies

GnomAD3 genomes AF: 0.00802 AC: 1219 AN: 151992 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00204 AC: 510 AN: 249502 AF XY: 0.00174

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.000863 AC: 1254 AN: 1452256 Hom.: 22 Cov.: 28 AF XY: 0.000776 AC XY: 561 AN XY: 723158

African (AFR) AF: 0.0284 AC: 946 AN: 33290

American (AMR) AF: 0.00168 AC: 75 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26098

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39624

South Asian (SAS) AF: 0.000198 AC: 17 AN: 86034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5748

European-Non Finnish (NFE) AF: 0.0000634 AC: 70 AN: 1103316

Other (OTH) AF: 0.00231 AC: 139 AN: 60056

GnomAD4 genome AF: 0.00808 AC: 1229 AN: 152110 Hom.: 14 Cov.: 32 AF XY: 0.00826 AC XY: 614 AN XY: 74356

African (AFR) AF: 0.0283 AC: 1174 AN: 41474

American (AMR) AF: 0.00262 AC: 40 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68008

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00314 Hom.: 7

Bravo AF: 0.00890

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.58
DANN	Benign	0.55
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs74032923; hg19: chr16-81954829;