rs138158454

Variant names:

• chr16-81912723-G-A
• rs138158454
• NM_002661.5:c.2054+7G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-81912723-G-A
• chr16-81912723-G-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.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:5
• Conservation: PhyloP100: -0.0130
• Publications: 3 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=-0.82).
• BP6: Variant 16-81912723-G-A is Benign according to our data. Variant chr16-81912723-G-A is described in ClinVar as Benign. ClinVar VariationId is 472894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4334 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.2054+7G>A		splice_region_variant, intron_variant	Intron 19 of 32	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.2054+7G>A		splice_region_variant, intron_variant	Intron 20 of 33		NP_001412678.1
PLCG2	NM_001425750.1	c.2054+7G>A		splice_region_variant, intron_variant	Intron 19 of 32		NP_001412679.1
PLCG2	NM_001425751.1	c.2054+7G>A		splice_region_variant, intron_variant	Intron 20 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.2054+7G>A		splice_region_variant, intron_variant	Intron 19 of 32	1	NM_002661.5	ENSP00000482457.1

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

GnomAD2 exomes AF: 0.0273 AC: 6111 AN: 223992 AF XY: 0.0282

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 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

African (AFR) AF: 0.00719 AC: 237 AN: 32940

American (AMR) AF: 0.0225 AC: 952 AN: 42398

Ashkenazi Jewish (ASJ) AF: 0.0476 AC: 1156 AN: 24266

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39262

South Asian (SAS) AF: 0.0108 AC: 888 AN: 82196

European-Finnish (FIN) AF: 0.0126 AC: 655 AN: 52136

Middle Eastern (MID) AF: 0.0244 AC: 138 AN: 5656

European-Non Finnish (NFE) AF: 0.0476 AC: 52454 AN: 1101774

Other (OTH) AF: 0.0367 AC: 2184 AN: 59506

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

African (AFR) AF: 0.00909 AC: 378 AN: 41602

American (AMR) AF: 0.0346 AC: 529 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 160 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00890 AC: 43 AN: 4832

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0434 AC: 2953 AN: 68034

Other (OTH) AF: 0.0440 AC: 93 AN: 2114

Alfa AF: 0.0319 Hom.: 47

Bravo AF: 0.0295

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

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	-0.82
CADD	Benign	0.091
DANN	Benign	0.41
PhyloP100		-0.013
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs138158454; hg19: chr16-81946328;