rs121913434

chr7-55174725-C-Gchr7-55174725-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005228.5(EGFR):c.2188C>G(p.Leu730Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L730R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 1.93

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_005228.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5	c.2188C>G	p.Leu730Val	missense_variant	19/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7	c.2188C>G	p.Leu730Val	missense_variant	19/28	1	NM_005228.5	P1
EGFR	ENST00000455089.5	c.2053C>G	p.Leu685Val	missense_variant	18/26	1
EGFR	ENST00000450046.2	c.2029C>G	p.Leu677Val	missense_variant	19/28	4
EGFR	ENST00000700145.1	c.538C>G	p.Leu180Val	missense_variant	6/9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Squamous cell carcinoma of the head and neck Other:1

drug response, no assertion criteria provided

literature only

Genetics, Bhagwan Mahavir Medical Research Centre

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Benign	0.39	T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.015
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.42	N;.;N
REVEL	Benign	0.19
Sift	Benign	0.41	T;.;T
Sift4G	Benign	0.88	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.72
MutPred		0.44		.;.;Gain of methylation at K728 (P = 0.0579);
MVP		0.75
MPC		1.1
ClinPred		0.83	D
GERP RS		4.7
Varity_R		0.53
gMVP		0.47

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: rs121913434; hg19: chr7-55242418;