NM_022970.4:c.-151+62G>C

Variant names:

• chr10-121597900-C-G
• rs4647913
• NM_022970.4:c.-151+62G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022970.4(FGFR2):​c.-151+62G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0664 in 389,128 control chromosomes in the GnomAD database, including 1,580 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.077 (743 hom., cov: 33)
  • Exomes 𝑓: 0.059 (837 hom.)
• Consequence: FGFR2 NM_022970.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.223
• Publications: 3 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: Genomics England PanelApp, G2P, Orphanet, ClinGen
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Genomics England PanelApp
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Crouzon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, G2P, ClinGen
• Jackson-Weiss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics, G2P
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

  Inheritance: AD Classification: STRONG Submitted by: G2P, Genomics England PanelApp
• familial scaphocephaly syndrome, McGillivray type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022970.4. 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.-151+62G>C		intron	N/A	NP_075259.4	P21802-3
	FGFR2	NM_000141.5	MANE Select	c.-151+62G>C		intron	N/A	NP_000132.3	P21802-1
	FGFR2	NM_001441087.1		c.-151+62G>C		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.-151+62G>C		intron	N/A	ENSP00000410294.2	P21802-3
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.-151+62G>C		intron	N/A	ENSP00000351276.6	P21802-1
	FGFR2	ENST00000369058.7	TSL:1	c.-151+62G>C		intron	N/A	ENSP00000358054.3	A0A5S6RJB7

Frequencies

GnomAD3 genomes AF: 0.0772 AC: 11750 AN: 152110 Hom.: 739 Cov.: 33

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.0654

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0617

GnomAD4 exome AF: 0.0593 AC: 14047 AN: 236900 Hom.: 837 AF XY: 0.0563 AC XY: 6763 AN XY: 120030

African (AFR) AF: 0.109 AC: 761 AN: 6980

American (AMR) AF: 0.181 AC: 1281 AN: 7072

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 123 AN: 8988

East Asian (EAS) AF: 0.197 AC: 4423 AN: 22458

South Asian (SAS) AF: 0.0550 AC: 115 AN: 2092

European-Finnish (FIN) AF: 0.101 AC: 2012 AN: 19876

Middle Eastern (MID) AF: 0.0128 AC: 16 AN: 1248

European-Non Finnish (NFE) AF: 0.0282 AC: 4303 AN: 152358

Other (OTH) AF: 0.0640 AC: 1013 AN: 15828

GnomAD4 genome AF: 0.0773 AC: 11774 AN: 152228 Hom.: 743 Cov.: 33 AF XY: 0.0830 AC XY: 6177 AN XY: 74412

African (AFR) AF: 0.114 AC: 4731 AN: 41562

American (AMR) AF: 0.137 AC: 2097 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.235 AC: 1200 AN: 5104

South Asian (SAS) AF: 0.0661 AC: 319 AN: 4826

European-Finnish (FIN) AF: 0.120 AC: 1269 AN: 10614

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0287 AC: 1950 AN: 68024

Other (OTH) AF: 0.0620 AC: 131 AN: 2112

Alfa AF: 0.0199 Hom.: 11

Bravo AF: 0.0853

Asia WGS AF: 0.138 AC: 480 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.3
DANN	Benign	0.64
PhyloP100		0.22
PromoterAI		0.036	Neutral
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4647913;

hg19: chr10-123357414;