rs2981452

Positions:

• chr10-121565883-G-C

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.110-179C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 695,198 control chromosomes in the GnomAD database, including 10,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3204 hom., cov: 32)
  • Exomes 𝑓: 0.16 (7499 hom.)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.516

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 10-121565883-G-C is Benign according to our data. Variant chr10-121565883-G-C is described in ClinVar as [Benign]. Clinvar id is 1281787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.110-179C>G		intron_variant		ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.110-179C>G		intron_variant		1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.110-179C>G		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.110-179C>G		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.110-179C>G		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.110-1304C>G		intron_variant		5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.110-179C>G		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.110-14424C>G		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.110-1304C>G		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.110-14424C>G		intron_variant		1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29543 AN: 151986 Hom.: 3199 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0456

Gnomad SAS AF: 0.0886

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.168

GnomAD4 exome AF: 0.160 AC: 86634 AN: 543094 Hom.: 7499 Cov.: 6 AF XY: 0.157 AC XY: 45012 AN XY: 286602

Gnomad4 AFR exome AF: 0.282

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.0631

Gnomad4 SAS exome AF: 0.0968

Gnomad4 FIN exome AF: 0.193

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.194 AC: 29570 AN: 152104 Hom.: 3204 Cov.: 32 AF XY: 0.193 AC XY: 14363 AN XY: 74350

Gnomad4 AFR AF: 0.280

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.0457

Gnomad4 SAS AF: 0.0885

Gnomad4 FIN AF: 0.208

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.167

Alfa AF: 0.200 Hom.: 403

Bravo AF: 0.189

Asia WGS AF: 0.0760 AC: 265 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 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.9
DANN	Benign	0.42

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: rs2981452; hg19: chr10-123325397;