7-55146655-C-T

Variant names:

• chr7-55146655-C-T
• rs2072454
• NM_005228.5:c.474C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005228.5(EGFR):​c.474C>T​(p.Asn158Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,613,822 control chromosomes in the GnomAD database, including 220,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (19503 hom., cov: 32)
  • Exomes 𝑓: 0.52 (201148 hom.)
• Consequence: EGFR NM_005228.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.905
• Publications: 87 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 7-55146655-C-T is Benign according to our data. Variant chr7-55146655-C-T is described in ClinVar as Benign. ClinVar VariationId is 259680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.905 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.526 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.474C>T	p.Asn158Asn	synonymous	Exon 4 of 28	NP_005219.2
	EGFR	NM_001346900.2		c.315C>T	p.Asn105Asn	synonymous	Exon 4 of 28	NP_001333829.1	C9JYS6
	EGFR	NM_001346898.2		c.474C>T	p.Asn158Asn	synonymous	Exon 4 of 27	NP_001333827.1	E7BSV0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	ENST00000275493.7	TSL:1 MANE Select	c.474C>T	p.Asn158Asn	synonymous	Exon 4 of 28	ENSP00000275493.2	P00533-1
	EGFR	ENST00000344576.7	TSL:1	c.474C>T	p.Asn158Asn	synonymous	Exon 4 of 16	ENSP00000345973.2	P00533-3
	EGFR	ENST00000342916.7	TSL:1	c.474C>T	p.Asn158Asn	synonymous	Exon 4 of 16	ENSP00000342376.3	P00533-4

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76735 AN: 151856 Hom.: 19469 Cov.: 32

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.503

GnomAD2 exomes AF: 0.511 AC: 128445 AN: 251406 AF XY: 0.511

Gnomad AFR exome AF: 0.497

Gnomad AMR exome AF: 0.523

Gnomad ASJ exome AF: 0.568

Gnomad EAS exome AF: 0.367

Gnomad FIN exome AF: 0.495

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.500

GnomAD4 exome AF: 0.523 AC: 764184 AN: 1461848 Hom.: 201148 Cov.: 63 AF XY: 0.523 AC XY: 380414 AN XY: 727232

African (AFR) AF: 0.501 AC: 16766 AN: 33480

American (AMR) AF: 0.524 AC: 23439 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 14804 AN: 26136

East Asian (EAS) AF: 0.333 AC: 13226 AN: 39698

South Asian (SAS) AF: 0.551 AC: 47529 AN: 86258

European-Finnish (FIN) AF: 0.493 AC: 26351 AN: 53408

Middle Eastern (MID) AF: 0.527 AC: 3038 AN: 5768

European-Non Finnish (NFE) AF: 0.528 AC: 587624 AN: 1111984

Other (OTH) AF: 0.520 AC: 31407 AN: 60396

GnomAD4 genome AF: 0.506 AC: 76824 AN: 151974 Hom.: 19503 Cov.: 32 AF XY: 0.500 AC XY: 37143 AN XY: 74264

African (AFR) AF: 0.499 AC: 20674 AN: 41468

American (AMR) AF: 0.494 AC: 7535 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1921 AN: 3466

East Asian (EAS) AF: 0.351 AC: 1806 AN: 5142

South Asian (SAS) AF: 0.543 AC: 2615 AN: 4812

European-Finnish (FIN) AF: 0.482 AC: 5086 AN: 10560

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.522 AC: 35510 AN: 67962

Other (OTH) AF: 0.507 AC: 1069 AN: 2108

Alfa AF: 0.516 Hom.: 83736

Bravo AF: 0.506

Asia WGS AF: 0.463 AC: 1612 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.9
DANN	Benign	0.69
PhyloP100		0.91
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: rs2072454; hg19: chr7-55214348; COSMIC: COSV51766078;