rs2288336

Variant names:

• chr10-121487098-G-A
• rs2288336
• NM_000141.5:c.2057+256C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000141.5(FGFR2):​c.2057+256C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 152,146 control chromosomes in the GnomAD database, including 18,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.47 (18493 hom., cov: 33)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.37
• Publications: 7 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: 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-121487098-G-A is Benign according to our data. Variant chr10-121487098-G-A is described in ClinVar as [Benign]. Clinvar id is 667900.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.2057+256C>T		intron_variant	Intron 15 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.2057+256C>T		intron_variant	Intron 15 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.2060+256C>T		intron_variant	Intron 15 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.2060+256C>T		intron_variant	Intron 14 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.2060+256C>T		intron_variant	Intron 15 of 16	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1790+256C>T		intron_variant	Intron 14 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1721+256C>T		intron_variant	Intron 12 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1715+256C>T		intron_variant	Intron 13 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1793+256C>T		intron_variant	Intron 14 of 16	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1373+256C>T		intron_variant	Intron 14 of 16	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.833+256C>T		intron_variant	Intron 7 of 8	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*1104+256C>T		intron_variant	Intron 14 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70966 AN: 152026 Hom.: 18480 Cov.: 33

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.492

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.467 AC: 71016 AN: 152146 Hom.: 18493 Cov.: 33 AF XY: 0.467 AC XY: 34760 AN XY: 74354

African (AFR) AF: 0.237 AC: 9853 AN: 41510

American (AMR) AF: 0.619 AC: 9468 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 2072 AN: 3472

East Asian (EAS) AF: 0.283 AC: 1465 AN: 5184

South Asian (SAS) AF: 0.542 AC: 2617 AN: 4826

European-Finnish (FIN) AF: 0.482 AC: 5084 AN: 10558

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.571 AC: 38824 AN: 67990

Other (OTH) AF: 0.492 AC: 1041 AN: 2116

Alfa AF: 0.526 Hom.: 13616

Bravo AF: 0.468

Asia WGS AF: 0.423 AC: 1471 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.9
DANN	Benign	0.55
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs2288336; hg19: chr10-123246612;