rs41293763
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000141.5(FGFR2):c.1673-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,610,884 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0019 ( 2 hom., cov: 31)
Exomes 𝑓: 0.0023 ( 11 hom. )
Consequence
FGFR2
NM_000141.5 intron
NM_000141.5 intron
Scores
2
Splicing: ADA: 0.0001020
2
Clinical Significance
Conservation
PhyloP100: 0.0230
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 -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 10-121496734-G-A is Benign according to our data. Variant chr10-121496734-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 298999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121496734-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00193 (293/151752) while in subpopulation SAS AF= 0.00356 (17/4770). AF 95% confidence interval is 0.00249. There are 2 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 Mitochondrial gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FGFR2 | NM_000141.5 | c.1673-12C>T | intron_variant | ENST00000358487.10 | NP_000132.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FGFR2 | ENST00000358487.10 | c.1673-12C>T | intron_variant | 1 | NM_000141.5 | ENSP00000351276.6 | ||||
| FGFR2 | ENST00000457416.7 | c.1676-12C>T | intron_variant | 1 | ENSP00000410294.2 | |||||
| FGFR2 | ENST00000369056.5 | c.1676-12C>T | intron_variant | 1 | ENSP00000358052.1 | |||||
| FGFR2 | ENST00000369058.7 | c.1676-12C>T | intron_variant | 1 | ENSP00000358054.3 | |||||
| FGFR2 | ENST00000613048.4 | c.1406-12C>T | intron_variant | 5 | ENSP00000484154.1 | |||||
| FGFR2 | ENST00000369061.8 | c.1337-12C>T | intron_variant | 1 | ENSP00000358057.4 | |||||
| FGFR2 | ENST00000369059.5 | c.1331-12C>T | intron_variant | 5 | ENSP00000358055.1 | |||||
| FGFR2 | ENST00000360144.7 | c.1409-12C>T | intron_variant | 2 | ENSP00000353262.3 | |||||
| FGFR2 | ENST00000478859.5 | c.989-12C>T | intron_variant | 1 | ENSP00000474011.1 | |||||
| FGFR2 | ENST00000429361.5 | c.449-12C>T | intron_variant | 5 | ENSP00000404219.1 | |||||
| FGFR2 | ENST00000604236.5 | n.*720-12C>T | intron_variant | 1 | ENSP00000474109.1 |
Frequencies
GnomAD3 genomes 0.00193 AC: 292AN: 151662Hom.: 2 Cov.: 31
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GnomAD3 exomes AF: 0.00227 AC: 569AN: 250560Hom.: 0 AF XY: 0.00238 AC XY: 322AN XY: 135448
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GnomAD4 exome AF: 0.00225 AC: 3284AN: 1459132Hom.: 11 Cov.: 32 AF XY: 0.00234 AC XY: 1701AN XY: 725902
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GnomAD4 genome 0.00193 AC: 293AN: 151752Hom.: 2 Cov.: 31 AF XY: 0.00180 AC XY: 133AN XY: 74086
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2019 | - - |
| Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 21, 2022 | - - |
FGFR2-related craniosynostosis Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | - - |
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
| Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at