10-121479598-G-A
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_001144915.2(FGFR2):c.2107C>T(p.Leu703Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,550,826 control chromosomes in the GnomAD database, including 235,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.44 ( 17607 hom., cov: 33)
Exomes 𝑓: 0.55 ( 218120 hom. )
Consequence
FGFR2
NM_001144915.2 synonymous
NM_001144915.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.19
Genes affected
FGFR2 (HGNC:3689): (fibroblast growth factor receptor 2) The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor, depending on the isoform. Mutations in this gene are associated with Crouzon syndrome, Pfeiffer syndrome, Craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. Multiple alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.65).
BP6
Variant 10-121479598-G-A is Benign according to our data. Variant chr10-121479598-G-A is described in ClinVar as [Benign]. Clinvar id is 298991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121479598-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=3.19 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FGFR2 | ENST00000358487 | c.*259C>T | 3_prime_UTR_variant | 18/18 | 1 | NM_000141.5 | ENSP00000351276.6 | |||
| FGFR2 | ENST00000457416 | c.*259C>T | 3_prime_UTR_variant | 18/18 | 1 | ENSP00000410294.2 | ||||
| FGFR2 | ENST00000613048 | c.*259C>T | 3_prime_UTR_variant | 17/17 | 5 | ENSP00000484154.1 | ||||
| FGFR2 | ENST00000369061 | c.*259C>T | 3_prime_UTR_variant | 15/15 | 1 | ENSP00000358057.4 | ||||
| FGFR2 | ENST00000478859 | c.*259C>T | 3_prime_UTR_variant | 17/17 | 1 | ENSP00000474011.1 | ||||
| FGFR2 | ENST00000604236.5 | n.*1772C>T | non_coding_transcript_exon_variant | 17/17 | 1 | ENSP00000474109.1 | ||||
| FGFR2 | ENST00000604236.5 | n.*1772C>T | 3_prime_UTR_variant | 17/17 | 1 | ENSP00000474109.1 | ||||
| FGFR2 | ENST00000369059.5 | c.*259C>T | downstream_gene_variant | 5 | ENSP00000358055.1 |
Frequencies
GnomAD3 genomes 0.444 AC: 67496AN: 151966Hom.: 17592 Cov.: 33
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GnomAD3 exomes AF: 0.555 AC: 85941AN: 154958Hom.: 25377 AF XY: 0.555 AC XY: 45461AN XY: 81928
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GnomAD4 exome AF: 0.552 AC: 772464AN: 1398742Hom.: 218120 Cov.: 42 AF XY: 0.554 AC XY: 381978AN XY: 689824
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GnomAD4 genome 0.444 AC: 67522AN: 152084Hom.: 17607 Cov.: 33 AF XY: 0.448 AC XY: 33284AN XY: 74344
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ClinVar
Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
| Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not provided Benign:2
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 09, 2018 | - - |
Crouzon syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Beare-Stevenson cutis gyrata syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Isolated Coronal Synostosis Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Craniosynostosis syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Saethre-Chotzen syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at