rs2071616

Positions:

• chr10-121520281-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 1262737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121520281-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.749-112G>A		intron_variant		ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.749-112G>A		intron_variant		1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.749-112G>A		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.749-112G>A		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.749-112G>A		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.482-112G>A		intron_variant		5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.749-4962G>A		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.404-112G>A		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.482-112G>A		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.65-112G>A		intron_variant		1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.404-112G>A		intron_variant		1		ENSP00000474109.1

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

Gnomad4 AFR exome AF: 0.0990

Gnomad4 AMR exome AF: 0.241

Gnomad4 ASJ exome AF: 0.260

Gnomad4 EAS exome AF: 0.0978

Gnomad4 SAS exome AF: 0.262

Gnomad4 FIN exome AF: 0.403

Gnomad4 NFE exome AF: 0.317

Gnomad4 OTH exome AF: 0.269

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

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.0916

Gnomad4 SAS AF: 0.258

Gnomad4 FIN AF: 0.414

Gnomad4 NFE AF: 0.324

Gnomad4 OTH AF: 0.243

Alfa AF: 0.273 Hom.: 1266

Bravo AF: 0.228

Asia WGS AF: 0.193 AC: 672 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.51

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: rs2071616; hg19: chr10-123279795; COSMIC: COSV60645478; COSMIC: COSV60645478;