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rs115583707

chr16-81927178-G-Achr16-81927178-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_002661.5(PLCG2):c.2514G>A(p.Gln838=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,603,218 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.010 ( 24 hom., cov: 32)
Exomes 𝑓: 0.00099 ( 21 hom. )

Consequence

PLCG2
NM_002661.5 splice_region, synonymous

Scores

2
Splicing: ADA: 0.9984
2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 9.32
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-81927178-G-A is Benign according to our data. Variant chr16-81927178-G-A is described in ClinVar as [Benign]. Clinvar id is 472898.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81927178-G-A is described in Lovd as [Benign].
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1530/152282) while in subpopulation AFR AF= 0.0356 (1478/41536). AF 95% confidence interval is 0.0341. There are 24 homozygotes in gnomad4. There are 743 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 1522 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLCG2NM_002661.5 linkuse as main transcriptc.2514G>A p.Gln838= splice_region_variant, synonymous_variant 23/33 ENST00000564138.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLCG2ENST00000564138.6 linkuse as main transcriptc.2514G>A p.Gln838= splice_region_variant, synonymous_variant 23/331 NM_002661.5 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0100
AC:
1522
AN:
152164
Hom.:
23
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0355
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00275
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00382
GnomAD3 exomes
AF:
0.00252
AC:
629
AN:
249366
Hom.:
11
AF XY:
0.00177
AC XY:
240
AN XY:
135292
show subpopulations
Gnomad AFR exome
AF:
0.0371
Gnomad AMR exome
AF:
0.00136
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.000986
AC:
1430
AN:
1450936
Hom.:
21
Cov.:
27
AF XY:
0.000841
AC XY:
608
AN XY:
722586
show subpopulations
Gnomad4 AFR exome
AF:
0.0365
Gnomad4 AMR exome
AF:
0.00161
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000544
Gnomad4 OTH exome
AF:
0.00200
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0100
AC:
1530
AN:
152282
Hom.:
24
Cov.:
32
AF XY:
0.00998
AC XY:
743
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.0356
Gnomad4 AMR
AF:
0.00275
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00378
Alfa
AF:
0.00147
Hom.:
7
Bravo
AF:
0.0115
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial cold autoinflammatory syndrome 3 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.34
Cadd
Benign
20
Dann
Benign
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.86
SpliceAI score (max)
0.090
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs115583707; hg19: chr16-81960783; API