10-121520044-T-C

Position:

• chr10-121520044-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000141.5(FGFR2):​c.874A>G​(p.Lys292Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.87

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a strand (size 6) in uniprot entity FGFR2_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000141.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR2. . Gene score misZ 2.402 (greater than the threshold 3.09). Trascript score misZ 4.4365 (greater than threshold 3.09). GenCC has associacion of gene with Pfeiffer syndrome type 3, Antley-Bixler syndrome, Pfeiffer syndrome type 2, Saethre-Chotzen syndrome, Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome type 1, LADD syndrome 1, Pfeiffer syndrome, bent bone dysplasia syndrome 1, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, familial scaphocephaly syndrome, McGillivray type, Apert syndrome, LADD syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 10-121520044-T-C is Pathogenic according to our data. Variant chr10-121520044-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13282.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-121520044-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.874A>G	p.Lys292Glu	missense_variant	7/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.874A>G	p.Lys292Glu	missense_variant	7/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.874A>G	p.Lys292Glu	missense_variant	7/18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.874A>G	p.Lys292Glu	missense_variant	6/17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.874A>G	p.Lys292Glu	missense_variant	7/17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.607A>G	p.Lys203Glu	missense_variant	6/17	5		ENSP00000484154.1
FGFR2	ENST00000369059.5	c.529A>G	p.Lys177Glu	missense_variant	5/16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.607A>G	p.Lys203Glu	missense_variant	6/17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.190A>G	p.Lys64Glu	missense_variant	6/17	1		ENSP00000474011.1
FGFR2	ENST00000369061.8	c.749-4725A>G		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000604236.5	n.529A>G		non_coding_transcript_exon_variant	5/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

FGFR2-related craniosynostosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 04, 2022

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 292 of the FGFR2 protein (p.Lys292Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Crouzon syndrome (PMID: 9152842, 25271085; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13282). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Crouzon syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;.;D;.;.;.;D;.;T;.;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;.;H;.;.;H;.;H;.;H;.;H;H;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.2	D;.;D;.;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;.;D;.;D;T;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.97	D;.;.;.;B;.;.;.;.;.;P;D;.;.
Vest4		0.84
MutPred		0.69		.;.;Loss of methylation at K292 (P = 0.0014);.;.;Loss of methylation at K292 (P = 0.0014);.;Loss of methylation at K292 (P = 0.0014);Loss of methylation at K292 (P = 0.0014);Loss of methylation at K292 (P = 0.0014);.;Loss of methylation at K292 (P = 0.0014);Loss of methylation at K292 (P = 0.0014);.;
MVP		0.97
MPC		1.6
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

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: rs121918500; hg19: chr10-123279558;