7-55146655-C-T

Position:

• chr7-55146655-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFR	NM_005228.5	c.474C>T	p.Asn158Asn	synonymous_variant	4/28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.474C>T	p.Asn158Asn	synonymous_variant	4/28	1	NM_005228.5	ENSP00000275493.2

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

GnomAD3 exomes AF: 0.511 AC: 128445 AN: 251406 Hom.: 33086 AF XY: 0.511 AC XY: 69383 AN XY: 135882

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 SAS exome AF: 0.551

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

Gnomad4 AFR exome AF: 0.501

Gnomad4 AMR exome AF: 0.524

Gnomad4 ASJ exome AF: 0.566

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.551

Gnomad4 FIN exome AF: 0.493

Gnomad4 NFE exome AF: 0.528

Gnomad4 OTH exome AF: 0.520

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

Gnomad4 AFR AF: 0.499

Gnomad4 AMR AF: 0.494

Gnomad4 ASJ AF: 0.554

Gnomad4 EAS AF: 0.351

Gnomad4 SAS AF: 0.543

Gnomad4 FIN AF: 0.482

Gnomad4 NFE AF: 0.522

Gnomad4 OTH AF: 0.507

Alfa AF: 0.516 Hom.: 40649

Bravo AF: 0.506

Asia WGS AF: 0.463 AC: 1612 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

EGFR-related lung cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2024

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.9
DANN	Benign	0.69

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

Other links and lift over

dbSNP: rs2072454; hg19: chr7-55214348; COSMIC: COSV51766078;