chr10-121483683-G-A

Variant names:

• chr10-121483683-G-A
• rs2278202
• NM_022970.4:c.2304+15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000141.5(FGFR2):​c.2301+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,591,672 control chromosomes in the GnomAD database, including 267,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (19202 hom., cov: 32)
  • Exomes 𝑓: 0.58 (248047 hom.)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.940
• Publications: 28 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-121483683-G-A is Benign according to our data. Variant chr10-121483683-G-A is described in ClinVar as Benign. ClinVar VariationId is 255317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

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.2304+15C>T		intron	N/A	NP_075259.4	P21802-3
	FGFR2	NM_000141.5	MANE Select	c.2301+15C>T		intron	N/A	NP_000132.3	P21802-1
	FGFR2	NM_001441087.1		c.2298+15C>T		intron	N/A	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.2304+15C>T		intron	N/A	ENSP00000410294.2	P21802-3
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.2301+15C>T		intron	N/A	ENSP00000351276.6	P21802-1
	FGFR2	ENST00000369056.5	TSL:1	c.2304+15C>T		intron	N/A	ENSP00000358052.1	P21802-17

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70861 AN: 151874 Hom.: 19185 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.494

GnomAD2 exomes AF: 0.560 AC: 138507 AN: 247130 AF XY: 0.565

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.760

Gnomad ASJ exome AF: 0.603

Gnomad EAS exome AF: 0.345

Gnomad FIN exome AF: 0.508

Gnomad NFE exome AF: 0.578

Gnomad OTH exome AF: 0.568

GnomAD4 exome AF: 0.580 AC: 835238 AN: 1439680 Hom.: 248047 Cov.: 26 AF XY: 0.582 AC XY: 417101 AN XY: 717164

African (AFR) AF: 0.169 AC: 5584 AN: 33016

American (AMR) AF: 0.748 AC: 33195 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 15595 AN: 25970

East Asian (EAS) AF: 0.366 AC: 14507 AN: 39594

South Asian (SAS) AF: 0.628 AC: 53449 AN: 85116

European-Finnish (FIN) AF: 0.509 AC: 27115 AN: 53240

Middle Eastern (MID) AF: 0.518 AC: 2912 AN: 5624

European-Non Finnish (NFE) AF: 0.595 AC: 649953 AN: 1092982

Other (OTH) AF: 0.551 AC: 32928 AN: 59734

GnomAD4 genome AF: 0.466 AC: 70901 AN: 151992 Hom.: 19202 Cov.: 32 AF XY: 0.470 AC XY: 34879 AN XY: 74274

African (AFR) AF: 0.182 AC: 7558 AN: 41470

American (AMR) AF: 0.647 AC: 9867 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2139 AN: 3472

East Asian (EAS) AF: 0.344 AC: 1770 AN: 5144

South Asian (SAS) AF: 0.624 AC: 3004 AN: 4816

European-Finnish (FIN) AF: 0.497 AC: 5240 AN: 10548

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39644 AN: 67972

Other (OTH) AF: 0.492 AC: 1039 AN: 2110

Alfa AF: 0.547 Hom.: 33629

Bravo AF: 0.464

Asia WGS AF: 0.479 AC: 1663 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Beare-Stevenson cutis gyrata syndrome (1)
-	-	1	Craniosynostosis syndrome (1)
-	-	1	Crouzon syndrome (1)
-	-	1	FGFR2-related craniosynostosis (1)
-	-	1	Isolated Coronal Synostosis (1)
-	-	1	not provided (1)
-	-	1	Saethre-Chotzen syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	15
DANN	Benign	0.71
PhyloP100		0.94
Mutation Taster		=99/1	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: rs2278202; hg19: chr10-123243197; COSMIC: COSV60638466; COSMIC: COSV60638466;