NM_005228.5:c.2300_2308dupCCAGCGTGG
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM4PP3
The NM_005228.5(EGFR):c.2300_2308dupCCAGCGTGG(p.Ala767_Val769dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as drug response (no stars). Synonymous variant affecting the same amino acid position (i.e. D770D) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Consequence
EGFR
NM_005228.5 disruptive_inframe_insertion
NM_005228.5 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.99
Publications
22 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]
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 23 uncertain in NM_005228.5
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_005228.5.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
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
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| EGFR | NM_005228.5 | MANE Select | c.2300_2308dupCCAGCGTGG | p.Ala767_Val769dup | disruptive_inframe_insertion | Exon 20 of 28 | NP_005219.2 | ||
| EGFR | NM_001346899.2 | c.2165_2173dupCCAGCGTGG | p.Ala722_Val724dup | disruptive_inframe_insertion | Exon 19 of 27 | NP_001333828.1 | |||
| EGFR | NM_001346900.2 | c.2141_2149dupCCAGCGTGG | p.Ala714_Val716dup | disruptive_inframe_insertion | Exon 20 of 28 | NP_001333829.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| EGFR | ENST00000275493.7 | TSL:1 MANE Select | c.2300_2308dupCCAGCGTGG | p.Ala767_Val769dup | disruptive_inframe_insertion | Exon 20 of 28 | ENSP00000275493.2 | ||
| EGFR | ENST00000455089.5 | TSL:1 | c.2165_2173dupCCAGCGTGG | p.Ala722_Val724dup | disruptive_inframe_insertion | Exon 19 of 26 | ENSP00000415559.1 | ||
| EGFR | ENST00000450046.2 | TSL:4 | c.2141_2149dupCCAGCGTGG | p.Ala714_Val716dup | disruptive_inframe_insertion | Exon 20 of 28 | ENSP00000413354.2 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 34 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152206
Hom.:
Cov.:
34
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
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Gnomad SAS
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Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
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GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74370 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
1
AN:
152206
Hom.:
Cov.:
34
AF XY:
AC XY:
0
AN XY:
74370
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
41452
American (AMR)
AF:
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5184
South Asian (SAS)
AF:
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68038
Other (OTH)
AF:
AC:
0
AN:
2086
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
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0.95
Allele balance
ClinVar
Significance: drug response
Submissions summary: Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Tyrosine kinase inhibitor response Other:1
Feb 24, 2010
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:drug response
Review Status:no assertion criteria provided
Collection Method:clinical testing
Likely Resistant
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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