rs2227983

Variant names:

• chr7-55161562-G-A
• rs2227983
• NM_005228.5:c.1562G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-55161562-G-A
• chr7-55161562-G-C
• chr7-55161562-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.23 (5008 hom., cov: 34)
  • Exomes 𝑓: 0.27 (57717 hom.)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:2
• Conservation: PhyloP100: -0.764
• Publications: 278 publications found

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 Gene-Disease associations (from GenCC):

• lung cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• non-small cell lung carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• inflammatory skin and bowel disease, neonatal, 2

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• neonatal inflammatory skin and bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 134021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005228.5. 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
	EGFR	NM_005228.5	MANE Select	c.1562G>A	p.Arg521Lys	missense	Exon 13 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.1427G>A	p.Arg476Lys	missense	Exon 12 of 27	NP_001333828.1
	EGFR	NM_001346900.2		c.1403G>A	p.Arg468Lys	missense	Exon 13 of 28	NP_001333829.1	C9JYS6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	ENST00000275493.7	TSL:1 MANE Select	c.1562G>A	p.Arg521Lys	missense	Exon 13 of 28	ENSP00000275493.2	P00533-1
	EGFR	ENST00000455089.5	TSL:1	c.1427G>A	p.Arg476Lys	missense	Exon 12 of 26	ENSP00000415559.1	Q504U8
	EGFR	ENST00000344576.7	TSL:1	c.1562G>A	p.Arg521Lys	missense	Exon 13 of 16	ENSP00000345973.2	P00533-3

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35477 AN: 152182 Hom.: 5007 Cov.: 34

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

GnomAD2 exomes AF: 0.292 AC: 73445 AN: 251436 AF XY: 0.298

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 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.: 37 AF XY: 0.274 AC XY: 199468 AN XY: 727236

African (AFR) AF: 0.0870 AC: 2914 AN: 33480

American (AMR) AF: 0.296 AC: 13247 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 8937 AN: 26136

East Asian (EAS) AF: 0.577 AC: 22893 AN: 39700

South Asian (SAS) AF: 0.341 AC: 29440 AN: 86258

European-Finnish (FIN) AF: 0.318 AC: 16971 AN: 53404

Middle Eastern (MID) AF: 0.295 AC: 1702 AN: 5766

European-Non Finnish (NFE) AF: 0.255 AC: 283703 AN: 1112008

Other (OTH) AF: 0.286 AC: 17285 AN: 60396

GnomAD4 genome AF: 0.233 AC: 35481 AN: 152300 Hom.: 5008 Cov.: 34 AF XY: 0.243 AC XY: 18061 AN XY: 74476

African (AFR) AF: 0.0909 AC: 3778 AN: 41582

American (AMR) AF: 0.287 AC: 4394 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1144 AN: 3472

East Asian (EAS) AF: 0.548 AC: 2835 AN: 5172

South Asian (SAS) AF: 0.356 AC: 1722 AN: 4832

European-Finnish (FIN) AF: 0.328 AC: 3474 AN: 10600

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17378 AN: 68010

Other (OTH) AF: 0.246 AC: 520 AN: 2116

Alfa AF: 0.248 Hom.: 10918

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (4)
-	-	2	not provided (2)
-	-	1	EGFR-related lung cancer (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inflammatory skin and bowel disease, neonatal, 2 (1)
-	-	1	Lung cancer (1)
-	-	-	Cholangiocarcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.18
DANN	Benign	0.59
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.000027	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.23	N
PhyloP100		-0.76
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.0050
Sift	Benign	0.93	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.041
MPC		0.52
ClinPred		0.0020	T
GERP RS		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.55
Mutation Taster		=97/3	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: rs2227983; hg19: chr7-55229255; COSMIC: COSV51770369; COSMIC: COSV51770369;