rs2228246

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002660.3(PLCG1):ā€‹c.835A>Gā€‹(p.Ser279Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,611,738 control chromosomes in the GnomAD database, including 21,108 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: š‘“ 0.14 ( 1713 hom., cov: 30)
Exomes š‘“: 0.16 ( 19395 hom. )

Consequence

PLCG1
NM_002660.3 missense

Scores

3
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.48
Variant links:
Genes affected
PLCG1 (HGNC:9065): (phospholipase C gamma 1) The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of receptor-mediated tyrosine kinase activators. For example, when activated by SRC, the encoded protein causes the Ras guanine nucleotide exchange factor RasGRP1 to translocate to the Golgi, where it activates Ras. Also, this protein has been shown to be a major substrate for heparin-binding growth factor 1 (acidic fibroblast growth factor)-activated tyrosine kinase. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0016117394).
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLCG1NM_002660.3 linkuse as main transcriptc.835A>G p.Ser279Gly missense_variant 9/32 ENST00000685551.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLCG1ENST00000685551.1 linkuse as main transcriptc.835A>G p.Ser279Gly missense_variant 9/32 NM_002660.3 P3P19174-2

Frequencies

GnomAD3 genomes
AF:
0.141
AC:
21419
AN:
151542
Hom.:
1713
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.103
Gnomad AMI
AF:
0.149
Gnomad AMR
AF:
0.125
Gnomad ASJ
AF:
0.133
Gnomad EAS
AF:
0.00386
Gnomad SAS
AF:
0.0421
Gnomad FIN
AF:
0.250
Gnomad MID
AF:
0.117
Gnomad NFE
AF:
0.170
Gnomad OTH
AF:
0.137
GnomAD3 exomes
AF:
0.138
AC:
34593
AN:
250750
Hom.:
2849
AF XY:
0.135
AC XY:
18356
AN XY:
135518
show subpopulations
Gnomad AFR exome
AF:
0.0999
Gnomad AMR exome
AF:
0.133
Gnomad ASJ exome
AF:
0.141
Gnomad EAS exome
AF:
0.00348
Gnomad SAS exome
AF:
0.0445
Gnomad FIN exome
AF:
0.250
Gnomad NFE exome
AF:
0.170
Gnomad OTH exome
AF:
0.150
GnomAD4 exome
AF:
0.156
AC:
228066
AN:
1460078
Hom.:
19395
Cov.:
32
AF XY:
0.154
AC XY:
111509
AN XY:
726384
show subpopulations
Gnomad4 AFR exome
AF:
0.100
Gnomad4 AMR exome
AF:
0.133
Gnomad4 ASJ exome
AF:
0.144
Gnomad4 EAS exome
AF:
0.00592
Gnomad4 SAS exome
AF:
0.0451
Gnomad4 FIN exome
AF:
0.248
Gnomad4 NFE exome
AF:
0.170
Gnomad4 OTH exome
AF:
0.138
GnomAD4 genome
AF:
0.141
AC:
21429
AN:
151660
Hom.:
1713
Cov.:
30
AF XY:
0.141
AC XY:
10465
AN XY:
74062
show subpopulations
Gnomad4 AFR
AF:
0.103
Gnomad4 AMR
AF:
0.125
Gnomad4 ASJ
AF:
0.133
Gnomad4 EAS
AF:
0.00387
Gnomad4 SAS
AF:
0.0426
Gnomad4 FIN
AF:
0.250
Gnomad4 NFE
AF:
0.170
Gnomad4 OTH
AF:
0.135
Alfa
AF:
0.156
Hom.:
5093
Bravo
AF:
0.131
TwinsUK
AF:
0.160
AC:
593
ALSPAC
AF:
0.167
AC:
642
ESP6500AA
AF:
0.101
AC:
447
ESP6500EA
AF:
0.157
AC:
1346
ExAC
AF:
0.136
AC:
16566
Asia WGS
AF:
0.0330
AC:
115
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.70
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.52
.;D
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.083
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.83
T;T
MetaRNN
Benign
0.0016
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.76
N;N
MutationTaster
Benign
0.24
P;P;P
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.040
Sift
Benign
0.18
T;T
Sift4G
Benign
0.41
T;T
Polyphen
0.0
.;B
Vest4
0.031
ClinPred
0.0050
T
GERP RS
4.6
Varity_R
0.053
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs2228246; hg19: chr20-39792063; COSMIC: COSV54814654; COSMIC: COSV54814654; API