rs2288336

chr10-121487098-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000141.5(FGFR2):c.2057+256C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 152,146 control chromosomes in the GnomAD database, including 18,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.47 (18493 hom., cov: 33)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.37

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-121487098-G-A is Benign according to our data. Variant chr10-121487098-G-A is described in ClinVar as [Benign]. Clinvar id is 667900.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_000141.5	c.2057+256C>T		intron_variant		ENST00000358487.10
FGFR2	NM_022970.4	c.2060+256C>T		intron_variant		ENST00000457416.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000358487.10	c.2057+256C>T		intron_variant		1	NM_000141.5	A2
FGFR2	ENST00000457416.7	c.2060+256C>T		intron_variant		1	NM_022970.4	P4

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70966 AN: 152026 Hom.: 18480 Cov.: 33

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.492

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.467 AC: 71016 AN: 152146 Hom.: 18493 Cov.: 33 AF XY: 0.467 AC XY: 34760 AN XY: 74354

Gnomad4 AFR AF: 0.237

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.597

Gnomad4 EAS AF: 0.283

Gnomad4 SAS AF: 0.542

Gnomad4 FIN AF: 0.482

Gnomad4 NFE AF: 0.571

Gnomad4 OTH AF: 0.492

Alfa AF: 0.532 Hom.: 8488

Bravo AF: 0.468

Asia WGS AF: 0.423 AC: 1471 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.9
Dann	Benign	0.55

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: rs2288336; hg19: chr10-123246612;