rs2017000

Variant names:

• chr7-55174916-A-G
• rs2017000
• NM_005228.5:c.2283+96A>G

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.2283+96A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 918,832 control chromosomes in the GnomAD database, including 47,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6020 hom., cov: 33)
  • Exomes 𝑓: 0.32 (41644 hom.)
• Consequence: EGFR NM_005228.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.389
• Publications: 20 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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 (BayesDel_noAF=-0.83).
• BP6: Variant 7-55174916-A-G is Benign according to our data. Variant chr7-55174916-A-G is described in ClinVar as Benign. ClinVar VariationId is 1238213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2283+96A>G		intron_variant	Intron 19 of 27	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2283+96A>G		intron_variant	Intron 19 of 27	1	NM_005228.5	ENSP00000275493.2
EGFR	ENST00000455089.5	c.2148+96A>G		intron_variant	Intron 18 of 25	1		ENSP00000415559.1
EGFR	ENST00000450046.2	c.2124+96A>G		intron_variant	Intron 19 of 27	4		ENSP00000413354.2
EGFR	ENST00000700145.1	c.630+96A>G		intron_variant	Intron 6 of 8			ENSP00000514824.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38668 AN: 151958 Hom.: 6023 Cov.: 33

Gnomad AFR AF: 0.0968

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.317 AC: 242894 AN: 766756 Hom.: 41644 AF XY: 0.319 AC XY: 128980 AN XY: 404826

African (AFR) AF: 0.0934 AC: 1841 AN: 19714

American (AMR) AF: 0.346 AC: 13505 AN: 39012

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 8039 AN: 21264

East Asian (EAS) AF: 0.638 AC: 22343 AN: 35020

South Asian (SAS) AF: 0.370 AC: 25936 AN: 70080

European-Finnish (FIN) AF: 0.366 AC: 17961 AN: 49120

Middle Eastern (MID) AF: 0.336 AC: 1478 AN: 4396

European-Non Finnish (NFE) AF: 0.285 AC: 140040 AN: 490856

Other (OTH) AF: 0.315 AC: 11751 AN: 37294

GnomAD4 genome AF: 0.254 AC: 38667 AN: 152076 Hom.: 6020 Cov.: 33 AF XY: 0.264 AC XY: 19618 AN XY: 74344

African (AFR) AF: 0.0967 AC: 4016 AN: 41522

American (AMR) AF: 0.298 AC: 4557 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1258 AN: 3470

East Asian (EAS) AF: 0.616 AC: 3183 AN: 5164

South Asian (SAS) AF: 0.386 AC: 1850 AN: 4798

European-Finnish (FIN) AF: 0.373 AC: 3947 AN: 10572

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18961 AN: 67948

Other (OTH) AF: 0.268 AC: 566 AN: 2110

Alfa AF: 0.269 Hom.: 13376

Bravo AF: 0.246

Asia WGS AF: 0.467 AC: 1623 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.17
DANN	Benign	0.49
PhyloP100		-0.39
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: rs2017000; hg19: chr7-55242609; COSMIC: COSV99288774;