rs2981461

Positions:

• chr10-121487523-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.1987-99G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 991,590 control chromosomes in the GnomAD database, including 160,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18780 hom., cov: 34)
  • Exomes 𝑓: 0.57 (141753 hom.)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.449

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=-0.89).
• BP6: Variant 10-121487523-C-T is Benign according to our data. Variant chr10-121487523-C-T is described in ClinVar as [Benign]. Clinvar id is 1221003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121487523-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1987-99G>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.1987-99G>A		intron_variant		1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1990-99G>A		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1990-99G>A		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1990-99G>A		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1720-99G>A		intron_variant		5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1651-99G>A		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1645-99G>A		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1723-99G>A		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1303-99G>A		intron_variant		1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.763-99G>A		intron_variant		5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*1034-99G>A		intron_variant		1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70737 AN: 151918 Hom.: 18768 Cov.: 34

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.620

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.498

GnomAD4 exome AF: 0.574 AC: 481593 AN: 839556 Hom.: 141753 AF XY: 0.576 AC XY: 250950 AN XY: 435622

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.704

Gnomad4 ASJ exome AF: 0.598

Gnomad4 EAS exome AF: 0.340

Gnomad4 SAS exome AF: 0.630

Gnomad4 FIN exome AF: 0.504

Gnomad4 NFE exome AF: 0.593

Gnomad4 OTH exome AF: 0.546

GnomAD4 genome AF: 0.465 AC: 70766 AN: 152034 Hom.: 18780 Cov.: 34 AF XY: 0.467 AC XY: 34743 AN XY: 74334

Gnomad4 AFR AF: 0.206

Gnomad4 AMR AF: 0.621

Gnomad4 ASJ AF: 0.616

Gnomad4 EAS AF: 0.302

Gnomad4 SAS AF: 0.624

Gnomad4 FIN AF: 0.491

Gnomad4 NFE AF: 0.577

Gnomad4 OTH AF: 0.497

Alfa AF: 0.549 Hom.: 17647

Bravo AF: 0.464

Asia WGS AF: 0.476 AC: 1654 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	-0.89
CADD	Benign	0.12
DANN	Benign	0.37

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: rs2981461; hg19: chr10-123247037; COSMIC: COSV60660478; COSMIC: COSV60660478;