10-121520281-C-T

Variant names:

• chr10-121520281-C-T
• rs2071616
• NM_022970.4:c.749-112G>A

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.749-112G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,131,798 control chromosomes in the GnomAD database, including 51,472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5686 hom., cov: 33)
  • Exomes 𝑓: 0.30 (45786 hom.)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.324
• Publications: 17 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=-0.63).
• BP6: Variant 10-121520281-C-T is Benign according to our data. Variant chr10-121520281-C-T is described in ClinVar as Benign. ClinVar VariationId is 1262737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.321 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.749-112G>A		intron	N/A	NP_075259.4	P21802-3
	FGFR2	NM_000141.5	MANE Select	c.749-112G>A		intron	N/A	NP_000132.3	P21802-1
	FGFR2	NM_001441087.1		c.749-112G>A		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.749-112G>A		intron	N/A	ENSP00000410294.2	P21802-3
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.749-112G>A		intron	N/A	ENSP00000351276.6	P21802-1
	FGFR2	ENST00000369056.5	TSL:1	c.749-112G>A		intron	N/A	ENSP00000358052.1	P21802-17

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38057 AN: 152040 Hom.: 5686 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.0916

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.243

GnomAD4 exome AF: 0.299 AC: 292708 AN: 979640 Hom.: 45786 AF XY: 0.298 AC XY: 144540 AN XY: 485376

African (AFR) AF: 0.0990 AC: 2239 AN: 22624

American (AMR) AF: 0.241 AC: 5439 AN: 22556

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 4531 AN: 17440

East Asian (EAS) AF: 0.0978 AC: 3258 AN: 33312

South Asian (SAS) AF: 0.262 AC: 14836 AN: 56530

European-Finnish (FIN) AF: 0.403 AC: 13622 AN: 33766

Middle Eastern (MID) AF: 0.201 AC: 618 AN: 3072

European-Non Finnish (NFE) AF: 0.317 AC: 236425 AN: 746712

Other (OTH) AF: 0.269 AC: 11740 AN: 43628

GnomAD4 genome AF: 0.250 AC: 38064 AN: 152158 Hom.: 5686 Cov.: 33 AF XY: 0.254 AC XY: 18899 AN XY: 74378

African (AFR) AF: 0.105 AC: 4354 AN: 41534

American (AMR) AF: 0.248 AC: 3796 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 904 AN: 3466

East Asian (EAS) AF: 0.0916 AC: 474 AN: 5172

South Asian (SAS) AF: 0.258 AC: 1244 AN: 4818

European-Finnish (FIN) AF: 0.414 AC: 4377 AN: 10560

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.324 AC: 22056 AN: 68002

Other (OTH) AF: 0.243 AC: 512 AN: 2108

Alfa AF: 0.237 Hom.: 3142

Bravo AF: 0.228

Asia WGS AF: 0.193 AC: 672 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.51
PhyloP100		0.32
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: rs2071616; hg19: chr10-123279795; COSMIC: COSV60645478; COSMIC: COSV60645478;