rs2912795

Variant names:

• chr10-121490734-G-A
• rs2912795
• NM_000141.5:c.1864-2621C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-121490734-G-A
• chr10-121490734-G-C
• chr10-121490734-G-T

Variant summary

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

The NM_000141.5(FGFR2):​c.1864-2621C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 151,920 control chromosomes in the GnomAD database, including 18,173 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 0.46 (18173 hom., cov: 32)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.197
• 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: 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1864-2621C>T		intron_variant	Intron 13 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1864-2621C>T		intron_variant	Intron 13 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1867-2621C>T		intron_variant	Intron 13 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1867-2621C>T		intron_variant	Intron 12 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1867-2621C>T		intron_variant	Intron 13 of 16	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1597-2621C>T		intron_variant	Intron 12 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1528-2621C>T		intron_variant	Intron 10 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1522-2621C>T		intron_variant	Intron 11 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1600-2621C>T		intron_variant	Intron 12 of 16	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1180-2621C>T		intron_variant	Intron 12 of 16	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.640-2621C>T		intron_variant	Intron 5 of 8	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*911-2621C>T		intron_variant	Intron 12 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69742 AN: 151802 Hom.: 18159 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.485

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

GnomAD4 genome AF: 0.459 AC: 69782 AN: 151920 Hom.: 18173 Cov.: 32 AF XY: 0.461 AC XY: 34253 AN XY: 74268

African (AFR) AF: 0.210 AC: 8713 AN: 41424

American (AMR) AF: 0.616 AC: 9399 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2018 AN: 3470

East Asian (EAS) AF: 0.300 AC: 1542 AN: 5144

South Asian (SAS) AF: 0.607 AC: 2921 AN: 4812

European-Finnish (FIN) AF: 0.473 AC: 4991 AN: 10544

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.568 AC: 38579 AN: 67956

Other (OTH) AF: 0.485 AC: 1021 AN: 2106

Alfa AF: 0.491 Hom.: 10622

Bravo AF: 0.459

Asia WGS AF: 0.464 AC: 1613 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.73
DANN	Benign	0.59
PhyloP100		-0.20
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: rs2912795; hg19: chr10-123250248;