rs1649200

Variant names:

• chr10-121484216-G-A
• rs1649200
• NM_000141.5:c.2196-413C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-121484216-G-A
• chr10-121484216-G-C

Variant summary

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

The NM_000141.5(FGFR2):​c.2196-413C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 151,986 control chromosomes in the GnomAD database, including 49,519 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 0.80 (49519 hom., cov: 31)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.721
• Publications: 8 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: Orphanet, ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Genomics England PanelApp
• Crouzon syndrome

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• LADD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Pfeiffer syndrome

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

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

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• 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: PanelApp Australia, Genomics England PanelApp
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.2196-413C>T		intron_variant	Intron 16 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.2196-413C>T		intron_variant	Intron 16 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.2199-413C>T		intron_variant	Intron 16 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.2199-413C>T		intron_variant	Intron 15 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.2199-413C>T		intron_variant	Intron 16 of 16	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1929-413C>T		intron_variant	Intron 15 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1860-413C>T		intron_variant	Intron 13 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1854-413C>T		intron_variant	Intron 14 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1932-413C>T		intron_variant	Intron 15 of 16	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1512-413C>T		intron_variant	Intron 15 of 16	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.971+1179C>T		intron_variant	Intron 8 of 8	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*1243-413C>T		intron_variant	Intron 15 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.802 AC: 121872 AN: 151868 Hom.: 49499 Cov.: 31

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.816

Gnomad AMR AF: 0.878

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.951

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.825

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

GnomAD4 genome AF: 0.802 AC: 121947 AN: 151986 Hom.: 49519 Cov.: 31 AF XY: 0.801 AC XY: 59505 AN XY: 74262

African (AFR) AF: 0.685 AC: 28349 AN: 41406

American (AMR) AF: 0.878 AC: 13409 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3049 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5156 AN: 5174

South Asian (SAS) AF: 0.951 AC: 4572 AN: 4810

European-Finnish (FIN) AF: 0.724 AC: 7640 AN: 10558

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.839 AC: 57044 AN: 67988

Other (OTH) AF: 0.825 AC: 1739 AN: 2108

Alfa AF: 0.830 Hom.: 155776

Bravo AF: 0.807

Asia WGS AF: 0.943 AC: 3278 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.38
DANN	Benign	0.37
PhyloP100		-0.72
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

Other links and lift over

dbSNP: rs1649200; hg19: chr10-123243730;