20-41168825-T-C

Variant names:

• chr20-41168825-T-C
• rs753381
• NM_002660.3:c.2438T>C

Variant summary

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

The NM_002660.3(PLCG1):​c.2438T>C​(p.Ile813Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 1,610,688 control chromosomes in the GnomAD database, including 281,299 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 0.67 (36168 hom., cov: 33)
  • Exomes 𝑓: 0.57 (245131 hom.)
• Consequence: PLCG1 NM_002660.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 95 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]

MIR6871 (HGNC:49964): (microRNA 6871) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.4687835E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002660.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG1	NM_002660.3	MANE Select	c.2438T>C	p.Ile813Thr	missense	Exon 21 of 32	NP_002651.2
	PLCG1	NM_182811.2		c.2438T>C	p.Ile813Thr	missense	Exon 21 of 32	NP_877963.1	P19174-1
	MIR6871	NR_106931.1		n.-198T>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG1	ENST00000685551.1	MANE Select	c.2438T>C	p.Ile813Thr	missense	Exon 21 of 32	ENSP00000508698.1	P19174-2
	PLCG1	ENST00000373271.5	TSL:1	c.2438T>C	p.Ile813Thr	missense	Exon 21 of 32	ENSP00000362368.1	P19174-1
	PLCG1	ENST00000244007.7	TSL:5	c.2438T>C	p.Ile813Thr	missense	Exon 22 of 33	ENSP00000244007.3	P19174-2

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101786 AN: 151998 Hom.: 36106 Cov.: 33

Gnomad AFR AF: 0.920

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.825

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.641

GnomAD2 exomes AF: 0.611 AC: 153388 AN: 250944 AF XY: 0.602

Gnomad AFR exome AF: 0.926

Gnomad AMR exome AF: 0.604

Gnomad ASJ exome AF: 0.579

Gnomad EAS exome AF: 0.813

Gnomad FIN exome AF: 0.583

Gnomad NFE exome AF: 0.547

Gnomad OTH exome AF: 0.602

GnomAD4 exome AF: 0.574 AC: 837726 AN: 1458572 Hom.: 245131 Cov.: 35 AF XY: 0.574 AC XY: 416768 AN XY: 725772

African (AFR) AF: 0.933 AC: 31183 AN: 33430

American (AMR) AF: 0.609 AC: 27216 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 15086 AN: 26104

East Asian (EAS) AF: 0.831 AC: 32992 AN: 39682

South Asian (SAS) AF: 0.599 AC: 51560 AN: 86140

European-Finnish (FIN) AF: 0.584 AC: 31178 AN: 53386

Middle Eastern (MID) AF: 0.607 AC: 3086 AN: 5088

European-Non Finnish (NFE) AF: 0.549 AC: 609525 AN: 1109858

Other (OTH) AF: 0.596 AC: 35900 AN: 60222

GnomAD4 genome AF: 0.670 AC: 101913 AN: 152116 Hom.: 36168 Cov.: 33 AF XY: 0.669 AC XY: 49774 AN XY: 74366

African (AFR) AF: 0.921 AC: 38244 AN: 41538

American (AMR) AF: 0.619 AC: 9466 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1963 AN: 3466

East Asian (EAS) AF: 0.825 AC: 4252 AN: 5156

South Asian (SAS) AF: 0.597 AC: 2879 AN: 4822

European-Finnish (FIN) AF: 0.576 AC: 6093 AN: 10584

Middle Eastern (MID) AF: 0.620 AC: 181 AN: 292

European-Non Finnish (NFE) AF: 0.545 AC: 37047 AN: 67946

Other (OTH) AF: 0.643 AC: 1355 AN: 2108

Alfa AF: 0.587 Hom.: 124937

Bravo AF: 0.684

TwinsUK AF: 0.545 AC: 2022

ALSPAC AF: 0.550 AC: 2120

ESP6500AA AF: 0.918 AC: 4043

ESP6500EA AF: 0.542 AC: 4662

ExAC AF: 0.614 AC: 74563

Asia WGS AF: 0.697 AC: 2423 AN: 3478

EpiCase AF: 0.539

EpiControl AF: 0.543

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.2	N
PhyloP100		1.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.21
Sift	Benign	0.55	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.057
ClinPred		0.0045	T
GERP RS		5.8
PromoterAI		0.016	Neutral
Varity_R		0.14
gMVP		0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs753381; hg19: chr20-39797465; COSMIC: COSV54816568; COSMIC: COSV54816568;