10-121496577-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_022970.4(FGFR2):c.1821C>G(p.Cys607Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C607C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FGFR2
NM_022970.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.59

Publications

4 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: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the FGFR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.402 (below the threshold of 3.09). Trascript score misZ: 4.3638 (above the threshold of 3.09). GenCC associations: The gene is linked to Pfeiffer syndrome type 3, Crouzon syndrome, Apert syndrome, Antley-Bixler syndrome, Beare-Stevenson cutis gyrata syndrome, Jackson-Weiss syndrome, bent bone dysplasia syndrome 1, Pfeiffer syndrome, Saethre-Chotzen syndrome, LADD syndrome 1, familial scaphocephaly syndrome, McGillivray type, LADD syndrome, Pfeiffer syndrome type 1, Pfeiffer syndrome type 2, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022970.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FGFR2	NM_022970.4	MANE Plus Clinical	c.1821C>G	p.Cys607Trp	missense	Exon 13 of 18	NP_075259.4
FGFR2	NM_000141.5	MANE Select	c.1818C>G	p.Cys606Trp	missense	Exon 13 of 18	NP_000132.3
FGFR2	NM_001441087.1		c.1815C>G	p.Cys605Trp	missense	Exon 13 of 18	NP_001428016.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.1821C>G	p.Cys607Trp	missense	Exon 13 of 18	ENSP00000410294.2
FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.1818C>G	p.Cys606Trp	missense	Exon 13 of 18	ENSP00000351276.6
FGFR2	ENST00000369056.5	TSL:1	c.1821C>G	p.Cys607Trp	missense	Exon 12 of 17	ENSP00000358052.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151980

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

Eigen

Benign

0.13

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

-0.015

PhyloP100

2.6

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-8.8

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.013

Polyphen

0.97

Vest4

0.76

MVP

0.96

MPC

2.1

ClinPred

0.99

GERP RS

2.4

Varity_R

0.95

gMVP

0.92

Mutation Taster

=6/94

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over