Genetic Variant NM_002660.3:c.2438T>C (chr20-41168825-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

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. 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.67 ( 36168 hom., cov: 33)

Exomes 𝑓: 0.57 ( 245131 hom. )

Consequence

PLCG1
NM_002660.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

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]

PLCG1 links:

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]

MIR6871 links:

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=1.4687835E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG1	NM_002660.3 link	c.2438T>C	p.Ile813Thr	missense_variant	Exon 21 of 32	ENST00000685551.1	NP_002651.2	P19174-2Q4LE43Q9UFY1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG1	ENST00000685551.1 link	c.2438T>C	p.Ile813Thr	missense_variant	Exon 21 of 32		NM_002660.3	ENSP00000508698.1		P19174-2

Frequencies

GnomAD3 genomes

AF:

0.670

AC:

101786

AN:

151998

Hom.:

36106

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.611

AC:

153388

AN:

250944

Hom.:

48472

AF XY:

0.602

AC XY:

81609

AN XY:

135626

show subpopulations

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 SAS exome

AF:

0.601

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.:

AF XY:

0.574

AC XY:

416768

AN XY:

725772

show subpopulations

Gnomad4 AFR exome

AF:

0.933

Gnomad4 AMR exome

AF:

0.609

Gnomad4 ASJ exome

AF:

0.578

Gnomad4 EAS exome

AF:

0.831

Gnomad4 SAS exome

AF:

0.599

Gnomad4 FIN exome

AF:

0.584

Gnomad4 NFE exome

AF:

0.549

Gnomad4 OTH exome

AF:

0.596

GnomAD4 genome

AF:

0.670

AC:

101913

AN:

152116

Hom.:

36168

Cov.:

AF XY:

0.669

AC XY:

49774

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.921

Gnomad4 AMR

AF:

0.619

Gnomad4 ASJ

AF:

0.566

Gnomad4 EAS

AF:

0.825

Gnomad4 SAS

AF:

0.597

Gnomad4 FIN

AF:

0.576

Gnomad4 NFE

AF:

0.545

Gnomad4 OTH

AF:

0.643

Alfa

AF:

0.571

Hom.:

55092

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.27

.;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.33

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.2

N;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

1.0

N;N

REVEL

Benign

0.21

Sift

Benign

0.55

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.057

ClinPred

0.0045

GERP RS

5.8

Varity_R

0.14

gMVP

0.27

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over