10-121565520-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000141.5(FGFR2):c.294G>A(p.Thr98Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00815 in 1,614,202 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0082 ( 92 hom. )

Consequence

FGFR2
NM_000141.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.0210

Publications

8 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Apert syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
Beare-Stevenson cutis gyrata syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Genomics England PanelApp
Crouzon syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, PanelApp Australia, Genomics England PanelApp, G2P
Jackson-Weiss syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
LADD syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Pfeiffer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
bent bone dysplasia syndrome 1
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
familial scaphocephaly syndrome, McGillivray type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
Saethre-Chotzen syndrome
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
Antley-Bixler syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
LADD syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Pfeiffer syndrome type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Pfeiffer syndrome type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Pfeiffer syndrome type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FGFR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 10-121565520-C-T is Benign according to our data. Variant chr10-121565520-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00744 (1133/152312) while in subpopulation NFE AF = 0.00957 (651/68026). AF 95% confidence interval is 0.00896. There are 3 homozygotes in GnomAd4. There are 617 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1133 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5 link	c.294G>A	p.Thr98Thr	synonymous_variant	Exon 3 of 18	ENST00000358487.10	NP_000132.3	P21802-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGFR2	ENST00000358487.10 link	c.294G>A	p.Thr98Thr	synonymous_variant	Exon 3 of 18	1	NM_000141.5	ENSP00000351276.6	P21802-1
FGFR2	ENST00000457416.7 link	c.294G>A	p.Thr98Thr	synonymous_variant	Exon 3 of 18	1		ENSP00000410294.2	P21802-3
FGFR2	ENST00000369056.5 link	c.294G>A	p.Thr98Thr	synonymous_variant	Exon 2 of 17	1		ENSP00000358052.1	P21802-17
FGFR2	ENST00000369058.7 link	c.294G>A	p.Thr98Thr	synonymous_variant	Exon 3 of 17	1		ENSP00000358054.3	A0A5S6RJB7
FGFR2	ENST00000369061.8 link	c.294G>A	p.Thr98Thr	synonymous_variant	Exon 2 of 15	1		ENSP00000358057.4	P21802-23
FGFR2	ENST00000613048.4 link	c.110-941G>A		intron_variant	Intron 2 of 16	5		ENSP00000484154.1	D2CGD1
FGFR2	ENST00000369059.5 link	c.110-14061G>A		intron_variant	Intron 2 of 15	5		ENSP00000358055.1	E7EVR7
FGFR2	ENST00000360144.7 link	c.110-941G>A		intron_variant	Intron 2 of 16	2		ENSP00000353262.3	P21802-22
FGFR2	ENST00000604236.5 link	n.110-14061G>A		intron_variant	Intron 2 of 16	1		ENSP00000474109.1	S4R3B2

Frequencies

GnomAD3 genomes

AF:

0.00745

AC:

1134

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0265

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00957

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00799

AC:

2010

AN:

251458

AF XY:

0.00800

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0248

Gnomad NFE exome

AF:

0.00984

Gnomad OTH exome

AF:

0.00961

GnomAD4 exome

AF:

0.00822

AC:

12023

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00815

AC XY:

5927

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

33480

American (AMR)

AF:

0.00342

AC:

153

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00264

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00452

AC:

390

AN:

86258

European-Finnish (FIN)

AF:

0.0265

AC:

1415

AN:

53418

Middle Eastern (MID)

AF:

0.00589

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00854

AC:

9494

AN:

1112010

Other (OTH)

AF:

0.00664

AC:

401

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

765

1530

2296

3061

3826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

306

612

918

1224

1530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00744

AC:

1133

AN:

152312

Hom.:

Cov.:

AF XY:

0.00828

AC XY:

617

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41586

American (AMR)

AF:

0.00504

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00291

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0265

AC:

281

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00957

AC:

651

AN:

68026

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00863

Hom.:

Bravo

AF:

0.00546

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00894

EpiControl

AF:

0.00812

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Oct 31, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 23, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 25, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FGFR2: BP4, BP7, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FGFR2-related craniosynostosis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Crouzon syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Beare-Stevenson cutis gyrata syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Isolated Coronal Synostosis

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Craniosynostosis syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Saethre-Chotzen syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

8.8

(source)

DANN

Benign

0.65

PhyloP100

0.021

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over