rs2228246

Variant names:

• chr20-41163423-A-G
• rs2228246
• NM_002660.3:c.835A>G

Variant summary

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

The NM_002660.3(PLCG1):​c.835A>G​(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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1713 hom., cov: 30)
  • Exomes 𝑓: 0.16 (19395 hom.)
• Consequence: PLCG1 NM_002660.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48
• Publications: 45 publications found

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]

PLCG1 Gene-Disease associations (from GenCC):

• immune dysregulation, autoimmunity, and autoinflammation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PLCG1	NM_002660.3	c.835A>G	p.Ser279Gly	missense_variant	Exon 9 of 32	ENST00000685551.1	NP_002651.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG1	ENST00000685551.1	c.835A>G	p.Ser279Gly	missense_variant	Exon 9 of 32		NM_002660.3	ENSP00000508698.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21419 AN: 151542 Hom.: 1713 Cov.: 30

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

GnomAD2 exomes AF: 0.138 AC: 34593 AN: 250750 AF XY: 0.135

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 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

African (AFR) AF: 0.100 AC: 3347 AN: 33442

American (AMR) AF: 0.133 AC: 5939 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3768 AN: 26110

East Asian (EAS) AF: 0.00592 AC: 235 AN: 39700

South Asian (SAS) AF: 0.0451 AC: 3889 AN: 86246

European-Finnish (FIN) AF: 0.248 AC: 13134 AN: 52926

Middle Eastern (MID) AF: 0.110 AC: 636 AN: 5758

European-Non Finnish (NFE) AF: 0.170 AC: 188819 AN: 1110880

Other (OTH) AF: 0.138 AC: 8299 AN: 60342

GnomAD4 genome AF: 0.141 AC: 21429 AN: 151660 Hom.: 1713 Cov.: 30 AF XY: 0.141 AC XY: 10465 AN XY: 74062

African (AFR) AF: 0.103 AC: 4238 AN: 41334

American (AMR) AF: 0.125 AC: 1913 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 461 AN: 3466

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5164

South Asian (SAS) AF: 0.0426 AC: 203 AN: 4766

European-Finnish (FIN) AF: 0.250 AC: 2627 AN: 10510

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11516 AN: 67864

Other (OTH) AF: 0.135 AC: 285 AN: 2104

Alfa AF: 0.155 Hom.: 9661

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
PhyloP100		2.5
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228246; hg19: chr20-39792063; COSMIC: COSV54814654; COSMIC: COSV54814654;