rs2227983

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005228.5(EGFR):c.1562G>A(p.Arg521Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,614,172 control chromosomes in the GnomAD database, including 62,725 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 5008 hom., cov: 34)

Exomes 𝑓: 0.27 ( 57717 hom. )

Consequence

EGFR
NM_005228.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:2

Conservation

PhyloP100: -0.764

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.7071093E-5).

BP6

Variant 7-55161562-G-A is Benign according to our data. Variant chr7-55161562-G-A is described in ClinVar as [Benign]. Clinvar id is 134021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-55161562-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFR	NM_005228.5 linkuse as main transcript	c.1562G>A	p.Arg521Lys	missense_variant	13/28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7 linkuse as main transcript	c.1562G>A	p.Arg521Lys	missense_variant	13/28	1	NM_005228.5	ENSP00000275493	P1	P00533-1

Frequencies

GnomAD3 genomes

AF:

0.233

AC:

35477

AN:

152182

Hom.:

5007

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0911

Gnomad AMI

AF:

0.161

Gnomad AMR

AF:

0.288

Gnomad ASJ

AF:

0.329

Gnomad EAS

AF:

0.547

Gnomad SAS

AF:

0.355

Gnomad FIN

AF:

0.328

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.246

GnomAD3 exomes

AF:

0.292

AC:

73445

AN:

251436

Hom.:

11842

AF XY:

0.298

AC XY:

40454

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0886

Gnomad AMR exome

AF:

0.298

Gnomad ASJ exome

AF:

0.338

Gnomad EAS exome

AF:

0.531

Gnomad SAS exome

AF:

0.344

Gnomad FIN exome

AF:

0.320

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.294

GnomAD4 exome

AF:

0.272

AC:

397092

AN:

1461872

Hom.:

57717

Cov.:

AF XY:

0.274

AC XY:

199468

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0870

Gnomad4 AMR exome

AF:

0.296

Gnomad4 ASJ exome

AF:

0.342

Gnomad4 EAS exome

AF:

0.577

Gnomad4 SAS exome

AF:

0.341

Gnomad4 FIN exome

AF:

0.318

Gnomad4 NFE exome

AF:

0.255

Gnomad4 OTH exome

AF:

0.286

GnomAD4 genome

AF:

0.233

AC:

35481

AN:

152300

Hom.:

5008

Cov.:

AF XY:

0.243

AC XY:

18061

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0909

Gnomad4 AMR

AF:

0.287

Gnomad4 ASJ

AF:

0.329

Gnomad4 EAS

AF:

0.548

Gnomad4 SAS

AF:

0.356

Gnomad4 FIN

AF:

0.328

Gnomad4 NFE

AF:

0.256

Gnomad4 OTH

AF:

0.246

Alfa

AF:

0.259

Hom.:

6712

Bravo

AF:

0.223

TwinsUK

AF:

0.261

AC:

969

ALSPAC

AF:

0.255

AC:

981

ESP6500AA

AF:

0.0887

AC:

391

ESP6500EA

AF:

0.261

AC:

2245

ExAC

AF:

0.287

AC:

34830

Asia WGS

AF:

0.411

AC:

1428

AN:

3478

EpiCase

AF:

0.267

EpiControl

AF:

0.262

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2019	This variant is associated with the following publications: (PMID: 18664296, 21292812, 19265688, 17575224, 19636371, 18726117, 24728327, 7937865, 27153395, 23594562) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

EGFR-related lung cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Lung cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Inflammatory skin and bowel disease, neonatal, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Cholangiocarcinoma

Other:1

other, no assertion criteria provided

research

Department of Surgery, Campus Charité Mitte Campus Virchow-klinikum, Charite-Universitaetsmedizin Berlin

Dec 10, 2022

No association with disease-free or overall survival after resection of intrahepatic Cholangiocarcinoma No association with disease-free or overall survival

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.18

DANN

Benign

0.59

DEOGEN2

Benign

0.21

T;.;T;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.36

T;T;T;T;T;T

MetaRNN

Benign

0.000027

T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.23

.;N;.;N;N;.

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.23

PROVEAN

Benign

0.25

N;N;.;N;N;.

REVEL

Benign

0.0050

Sift

Benign

0.93

T;T;.;T;T;.

Sift4G

Benign

0.42

T;T;T;T;T;.

Polyphen

0.0

B;B;.;B;B;.

Vest4

0.041

MPC

0.52

ClinPred

0.0020

GERP RS

-5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.55

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over