rs12446319

Variant names:

• chr16-81741193-T-C
• rs12446319
• NM_001425749.1:c.-145+1808T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001425749.1(PLCG2):​c.-145+1808T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 151,934 control chromosomes in the GnomAD database, including 13,865 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (13865 hom., cov: 31)
• Consequence: PLCG2 NM_001425749.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 10 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

LOC105369213 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_001425749.1	c.-145+1808T>C		intron_variant	Intron 1 of 33		NP_001412678.1
PLCG2	NM_001425750.1	c.-48+1808T>C		intron_variant	Intron 1 of 32		NP_001412679.1
PLCG2	NM_001425751.1	c.-145+1757T>C		intron_variant	Intron 1 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000565054.7	c.-145+1808T>C		intron_variant	Intron 1 of 33	5		ENSP00000520638.1
PLCG2	ENST00000697580.2	c.-48+1808T>C		intron_variant	Intron 1 of 32			ENSP00000520637.1
PLCG2	ENST00000563954.6	n.414+1757T>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63868 AN: 151816 Hom.: 13862 Cov.: 31

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.411

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.421 AC: 63902 AN: 151934 Hom.: 13865 Cov.: 31 AF XY: 0.430 AC XY: 31949 AN XY: 74250

African (AFR) AF: 0.334 AC: 13842 AN: 41424

American (AMR) AF: 0.445 AC: 6780 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1497 AN: 3466

East Asian (EAS) AF: 0.729 AC: 3762 AN: 5158

South Asian (SAS) AF: 0.616 AC: 2958 AN: 4804

European-Finnish (FIN) AF: 0.494 AC: 5224 AN: 10570

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.419 AC: 28481 AN: 67952

Other (OTH) AF: 0.413 AC: 870 AN: 2106

Alfa AF: 0.420 Hom.: 44339

Bravo AF: 0.411

Asia WGS AF: 0.624 AC: 2169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.75
DANN	Benign	0.35
PhyloP100		-1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12446319; hg19: chr16-81774798;