rs1258584689

Variant names:

• chr10-121520095-C-G
• rs1258584689
• NM_022970.4:c.823G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-121520095-C-G
• chr10-121520095-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000141.5(FGFR2):​c.823G>C​(p.Glu275Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000141.5
• 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: 4.4365 (above the threshold of 3.09). GenCC associations: The gene is linked to bent bone dysplasia syndrome 1, Crouzon syndrome, Beare-Stevenson cutis gyrata syndrome, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, Apert syndrome, familial scaphocephaly syndrome, McGillivray type, Pfeiffer syndrome, Jackson-Weiss syndrome, Saethre-Chotzen syndrome, LADD syndrome, Antley-Bixler syndrome, LADD syndrome 1, Pfeiffer syndrome type 2, Pfeiffer syndrome type 3, Pfeiffer syndrome type 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35259572).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000141.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	NM_022970.4	MANE Plus Clinical	c.823G>C	p.Glu275Gln	missense	Exon 7 of 18	NP_075259.4	P21802-3
	FGFR2	NM_000141.5	MANE Select	c.823G>C	p.Glu275Gln	missense	Exon 7 of 18	NP_000132.3	P21802-1
	FGFR2	NM_001441087.1		c.823G>C	p.Glu275Gln	missense	Exon 7 of 18	NP_001428016.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.823G>C	p.Glu275Gln	missense	Exon 7 of 18	ENSP00000410294.2	P21802-3
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.823G>C	p.Glu275Gln	missense	Exon 7 of 18	ENSP00000351276.6	P21802-1
	FGFR2	ENST00000369056.5	TSL:1	c.823G>C	p.Glu275Gln	missense	Exon 6 of 17	ENSP00000358052.1	P21802-17

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251414 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	FGFR2-related craniosynostosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	0.81	L
PhyloP100		2.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.13
Sift	Benign	0.054	T
Sift4G	Benign	0.26	T
Polyphen		0.094	B
Vest4		0.28
MutPred		0.49		Loss of sheet (P = 0.1398)
MVP		0.73
MPC		0.77
ClinPred		0.47	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.86
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs1258584689; hg19: chr10-123279609;