Genetic Variant FGFR2:c.*259C>T (chr10-121479598-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.19

Publications

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

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 298991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144915.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGFR2	NM_022970.4	MANE Plus Clinical	c.*259C>T		3_prime_UTR	Exon 18 of 18	NP_075259.4	P21802-3
FGFR2	NM_000141.5	MANE Select	c.*259C>T		3_prime_UTR	Exon 18 of 18	NP_000132.3	P21802-1
FGFR2	NM_001144915.2		c.2107C>T	p.Leu703Leu	synonymous	Exon 17 of 17	NP_001138387.1	P21802-21

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.*259C>T	3_prime_UTR	Exon 18 of 18	ENSP00000410294.2	P21802-3
FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.*259C>T	3_prime_UTR	Exon 18 of 18	ENSP00000351276.6	P21802-1
FGFR2	ENST00000613048.4	TSL:5	c.*259C>T	3_prime_UTR	Exon 17 of 17	ENSP00000484154.1	D2CGD1

Frequencies

GnomAD3 genomes

AF:

0.444

AC:

67496

AN:

151966

Hom.:

17592

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.492

Gnomad AMR

AF:

0.633

Gnomad ASJ

AF:

0.589

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.599

Gnomad FIN

AF:

0.493

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.554

Gnomad OTH

AF:

0.479

GnomAD2 exomes

AF:

0.555

AC:

85941

AN:

154958

AF XY:

0.555

show subpopulations

Gnomad AFR exome

AF:

0.147

Gnomad AMR exome

AF:

0.750

Gnomad ASJ exome

AF:

0.563

Gnomad EAS exome

AF:

0.380

Gnomad FIN exome

AF:

0.501

Gnomad NFE exome

AF:

0.557

Gnomad OTH exome

AF:

0.559

GnomAD4 exome

AF:

0.552

AC:

772464

AN:

1398742

Hom.:

218120

Cov.:

AF XY:

0.554

AC XY:

381978

AN XY:

689824

show subpopulations

African (AFR)

AF:

0.143

AC:

4528

AN:

31568

American (AMR)

AF:

0.732

AC:

26118

AN:

35664

Ashkenazi Jewish (ASJ)

AF:

0.561

AC:

14122

AN:

25172

East Asian (EAS)

AF:

0.391

AC:

13964

AN:

35720

South Asian (SAS)

AF:

0.596

AC:

47204

AN:

79180

European-Finnish (FIN)

AF:

0.501

AC:

24692

AN:

49272

Middle Eastern (MID)

AF:

0.480

AC:

2735

AN:

5696

European-Non Finnish (NFE)

AF:

0.564

AC:

608675

AN:

1078512

Other (OTH)

AF:

0.525

AC:

30426

AN:

57958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

16855

33710

50564

67419

84274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17148

34296

51444

68592

85740

<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:

0.444

AC:

67522

AN:

152084

Hom.:

17607

Cov.:

AF XY:

0.448

AC XY:

33284

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.157

AC:

6506

AN:

41500

American (AMR)

AF:

0.633

AC:

9671

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

2039

AN:

3464

East Asian (EAS)

AF:

0.373

AC:

1931

AN:

5180

South Asian (SAS)

AF:

0.600

AC:

2888

AN:

4812

European-Finnish (FIN)

AF:

0.493

AC:

5204

AN:

10566

Middle Eastern (MID)

AF:

0.497

AC:

146

AN:

294

European-Non Finnish (NFE)

AF:

0.554

AC:

37681

AN:

67980

Other (OTH)

AF:

0.477

AC:

1008

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1695

3389

5084

6778

8473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

614

1228

1842

2456

3070

<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:

0.525

Hom.:

42631

Bravo

AF:

0.442

Asia WGS

AF:

0.476

AC:

1652

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Beare-Stevenson cutis gyrata syndrome (1)

Craniosynostosis syndrome (1)

Crouzon syndrome (1)

Isolated Coronal Synostosis (1)

Saethre-Chotzen syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

3.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over