Variant chr7-55019282-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005228.5(EGFR):c.5G>A(p.Arg2Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000222 in 1,351,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

EGFR
NM_005228.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.62

Variant links:

Genes affected

EGFR (HGNC:3236): (epidermal growth factor receptor) The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor, thus inducing receptor dimerization and tyrosine autophosphorylation leading to cell proliferation. Mutations in this gene are associated with lung cancer. EGFR is a component of the cytokine storm which contributes to a severe form of Coronavirus Disease 2019 (COVID-19) resulting from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). [provided by RefSeq, Jul 2020]

EGFR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5 linkuse as main transcript	c.5G>A	p.Arg2Gln	missense_variant	1/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7 linkuse as main transcript	c.5G>A	p.Arg2Gln	missense_variant	1/28	1	NM_005228.5	P1	P00533-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000222

AC:

AN:

1351030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

669702

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000285

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

EGFR-related lung cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with EGFR-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 2 of the EGFR protein (p.Arg2Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

T;.;T;.;.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.079

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.78

T;T;T;T;T;T

M_CAP

Pathogenic

0.99

MetaRNN

Uncertain

0.50

D;D;D;D;D;D

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.90

.;L;.;L;L;L

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.28

N;N;.;N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.014

D;D;.;D;D;D

Sift4G

Uncertain

0.030

D;T;D;T;T;D

Polyphen

0.53

P;P;.;P;P;B

Vest4

0.21

MutPred

0.23

Loss of methylation at R2 (P = 0.0128);Loss of methylation at R2 (P = 0.0128);Loss of methylation at R2 (P = 0.0128);Loss of methylation at R2 (P = 0.0128);Loss of methylation at R2 (P = 0.0128);Loss of methylation at R2 (P = 0.0128);

MVP

0.81

MPC

1.4

ClinPred

0.80

GERP RS

4.3

Varity_R

0.15

gMVP

0.50

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over