10-121538644-T-C

Position:

• chr10-121538644-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000141.5(FGFR2):​c.696A>G​(p.Val232Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 1,613,866 control chromosomes in the GnomAD database, including 488,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45069 hom., cov: 31)
  • Exomes 𝑓: 0.78 (443218 hom.)
• Consequence: FGFR2 NM_000141.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.206

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 10-121538644-T-C is Benign according to our data. Variant chr10-121538644-T-C is described in ClinVar as [Benign]. Clinvar id is 255319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121538644-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.206 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.696A>G	p.Val232Val	synonymous_variant	6/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.696A>G	p.Val232Val	synonymous_variant	6/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.696A>G	p.Val232Val	synonymous_variant	6/18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.696A>G	p.Val232Val	synonymous_variant	5/17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.696A>G	p.Val232Val	synonymous_variant	6/17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.429A>G	p.Val143Val	synonymous_variant	5/17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.696A>G	p.Val232Val	synonymous_variant	5/15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.351A>G	p.Val117Val	synonymous_variant	4/16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.429A>G	p.Val143Val	synonymous_variant	5/17	2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.351A>G		non_coding_transcript_exon_variant	4/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116849 AN: 151958 Hom.: 45027 Cov.: 31

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.829

Gnomad EAS AF: 0.908

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.825

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.779

GnomAD3 exomes AF: 0.782 AC: 196571 AN: 251368 Hom.: 77295 AF XY: 0.780 AC XY: 105984 AN XY: 135856

Gnomad AFR exome AF: 0.750

Gnomad AMR exome AF: 0.804

Gnomad ASJ exome AF: 0.815

Gnomad EAS exome AF: 0.923

Gnomad SAS exome AF: 0.743

Gnomad FIN exome AF: 0.755

Gnomad NFE exome AF: 0.769

Gnomad OTH exome AF: 0.792

GnomAD4 exome AF: 0.778 AC: 1136925 AN: 1461792 Hom.: 443218 Cov.: 55 AF XY: 0.777 AC XY: 564980 AN XY: 727200

Gnomad4 AFR exome AF: 0.756

Gnomad4 AMR exome AF: 0.799

Gnomad4 ASJ exome AF: 0.819

Gnomad4 EAS exome AF: 0.904

Gnomad4 SAS exome AF: 0.746

Gnomad4 FIN exome AF: 0.754

Gnomad4 NFE exome AF: 0.775

Gnomad4 OTH exome AF: 0.793

GnomAD4 genome AF: 0.769 AC: 116950 AN: 152074 Hom.: 45069 Cov.: 31 AF XY: 0.768 AC XY: 57087 AN XY: 74350

Gnomad4 AFR AF: 0.752

Gnomad4 AMR AF: 0.783

Gnomad4 ASJ AF: 0.829

Gnomad4 EAS AF: 0.908

Gnomad4 SAS AF: 0.744

Gnomad4 FIN AF: 0.751

Gnomad4 NFE AF: 0.767

Gnomad4 OTH AF: 0.780

Alfa AF: 0.771 Hom.: 74982

Bravo AF: 0.775

Asia WGS AF: 0.808 AC: 2809 AN: 3478

EpiCase AF: 0.779

EpiControl AF: 0.788

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

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	-0.43
CADD	Benign	10
DANN	Benign	0.77

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: rs1047100; hg19: chr10-123298158; COSMIC: COSV100335254;