NM_005228.5:c.2184+100C>T

Variant names:

• chr7-55174143-C-T
• rs17290336
• NM_005228.5:c.2184+100C>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.2184+100C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,513,934 control chromosomes in the GnomAD database, including 1,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (225 hom., cov: 33)
  • Exomes 𝑓: 0.041 (1302 hom.)
• Consequence: EGFR NM_005228.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.765
• Publications: 6 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=-0.86).
• BP6: Variant 7-55174143-C-T is Benign according to our data. Variant chr7-55174143-C-T is described in ClinVar as [Benign]. Clinvar id is 1228216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2184+100C>T		intron_variant	Intron 18 of 27	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2184+100C>T		intron_variant	Intron 18 of 27	1	NM_005228.5	ENSP00000275493.2
EGFR	ENST00000455089.5	c.2049+100C>T		intron_variant	Intron 17 of 25	1		ENSP00000415559.1
EGFR	ENST00000450046.2	c.2025+100C>T		intron_variant	Intron 18 of 27	4		ENSP00000413354.2
EGFR	ENST00000700145.1	c.531+100C>T		intron_variant	Intron 5 of 8			ENSP00000514824.1

Frequencies

GnomAD3 genomes AF: 0.0509 AC: 7743 AN: 152210 Hom.: 227 Cov.: 33

Gnomad AFR AF: 0.0783

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0426

Gnomad ASJ AF: 0.0766

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0461

Gnomad OTH AF: 0.0569

GnomAD4 exome AF: 0.0413 AC: 56217 AN: 1361606 Hom.: 1302 AF XY: 0.0409 AC XY: 27607 AN XY: 675406

African (AFR) AF: 0.0808 AC: 2468 AN: 30560

American (AMR) AF: 0.0327 AC: 1149 AN: 35118

Ashkenazi Jewish (ASJ) AF: 0.0678 AC: 1619 AN: 23868

East Asian (EAS) AF: 0.0000786 AC: 3 AN: 38190

South Asian (SAS) AF: 0.0233 AC: 1827 AN: 78304

European-Finnish (FIN) AF: 0.0192 AC: 916 AN: 47790

Middle Eastern (MID) AF: 0.0689 AC: 308 AN: 4470

European-Non Finnish (NFE) AF: 0.0432 AC: 45257 AN: 1046872

Other (OTH) AF: 0.0473 AC: 2670 AN: 56434

GnomAD4 genome AF: 0.0508 AC: 7745 AN: 152328 Hom.: 225 Cov.: 33 AF XY: 0.0491 AC XY: 3656 AN XY: 74494

African (AFR) AF: 0.0782 AC: 3250 AN: 41568

American (AMR) AF: 0.0425 AC: 651 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0766 AC: 266 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0220 AC: 106 AN: 4828

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10620

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0461 AC: 3136 AN: 68026

Other (OTH) AF: 0.0568 AC: 120 AN: 2112

Alfa AF: 0.0532 Hom.: 34

Bravo AF: 0.0549

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.43
PhyloP100		-0.77
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: rs17290336; hg19: chr7-55241836; COSMIC: COSV51776814;