rs2278202

Positions:

• chr10-121483683-G-A
• chr10-121483683-G-C
• chr10-121483683-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000141.5(FGFR2):​c.2301+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,591,672 control chromosomes in the GnomAD database, including 267,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (19202 hom., cov: 32)
  • Exomes 𝑓: 0.58 (248047 hom.)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.940

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]

FGFR2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-121483683-G-A is Benign according to our data. Variant chr10-121483683-G-A is described in ClinVar as [Benign]. Clinvar id is 255317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121483683-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.2301+15C>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.2301+15C>T		intron_variant		1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.2304+15C>T		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.2304+15C>T		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000613048.4	c.2034+15C>T		intron_variant		5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1965+15C>T		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1959+15C>T		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.2037+15C>T		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1617+15C>T		intron_variant		1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.971+1712C>T		intron_variant		5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*1348+15C>T		intron_variant		1		ENSP00000474109.1
FGFR2	ENST00000369058.7	c.*15C>T		downstream_gene_variant		1		ENSP00000358054.3

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70861 AN: 151874 Hom.: 19185 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.494

GnomAD3 exomes AF: 0.560 AC: 138507 AN: 247130 Hom.: 41301 AF XY: 0.565 AC XY: 75282 AN XY: 133264

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.760

Gnomad ASJ exome AF: 0.603

Gnomad EAS exome AF: 0.345

Gnomad SAS exome AF: 0.626

Gnomad FIN exome AF: 0.508

Gnomad NFE exome AF: 0.578

Gnomad OTH exome AF: 0.568

GnomAD4 exome AF: 0.580 AC: 835238 AN: 1439680 Hom.: 248047 Cov.: 26 AF XY: 0.582 AC XY: 417101 AN XY: 717164

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.748

Gnomad4 ASJ exome AF: 0.601

Gnomad4 EAS exome AF: 0.366

Gnomad4 SAS exome AF: 0.628

Gnomad4 FIN exome AF: 0.509

Gnomad4 NFE exome AF: 0.595

Gnomad4 OTH exome AF: 0.551

GnomAD4 genome AF: 0.466 AC: 70901 AN: 151992 Hom.: 19202 Cov.: 32 AF XY: 0.470 AC XY: 34879 AN XY: 74274

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.647

Gnomad4 ASJ AF: 0.616

Gnomad4 EAS AF: 0.344

Gnomad4 SAS AF: 0.624

Gnomad4 FIN AF: 0.497

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.492

Alfa AF: 0.558 Hom.: 26937

Bravo AF: 0.464

Asia WGS AF: 0.479 AC: 1663 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

FGFR2-related craniosynostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	15
DANN	Benign	0.71

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: rs2278202; hg19: chr10-123243197; COSMIC: COSV60638466; COSMIC: COSV60638466;