rs1219648

Variant names:

• chr10-121586676-A-G
• rs1219648
• NM_022970.4:c.109+7033T>C

Your query was ambiguous. Multiple possible variants found:

• chr10-121586676-A-G
• chr10-121586676-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022970.4(FGFR2):​c.109+7033T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 152,050 control chromosomes in the GnomAD database, including 12,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.41 (12688 hom., cov: 33)
• Consequence: FGFR2 NM_022970.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.442
• Publications: 197 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-121586676-A-G is Benign according to our data. Variant chr10-121586676-A-G is described in ClinVar as Benign. ClinVar VariationId is 1663397.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_022970.4	c.109+7033T>C		intron_variant	Intron 2 of 17	ENST00000457416.7	NP_075259.4
FGFR2	NM_000141.5	c.109+7033T>C		intron_variant	Intron 2 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000457416.7	c.109+7033T>C		intron_variant	Intron 2 of 17	1	NM_022970.4	ENSP00000410294.2
FGFR2	ENST00000358487.10	c.109+7033T>C		intron_variant	Intron 2 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000369056.5	c.109+7033T>C		intron_variant	Intron 1 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.109+7033T>C		intron_variant	Intron 2 of 16	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.109+7033T>C		intron_variant	Intron 2 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.109+7033T>C		intron_variant	Intron 1 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.109+7033T>C		intron_variant	Intron 2 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.109+7033T>C		intron_variant	Intron 2 of 16	2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.109+7033T>C		intron_variant	Intron 2 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.408 AC: 62043 AN: 151932 Hom.: 12679 Cov.: 33

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.408

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

GnomAD4 genome AF: 0.408 AC: 62074 AN: 152050 Hom.: 12688 Cov.: 33 AF XY: 0.411 AC XY: 30552 AN XY: 74344

African (AFR) AF: 0.426 AC: 17675 AN: 41464

American (AMR) AF: 0.411 AC: 6282 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1445 AN: 3472

East Asian (EAS) AF: 0.378 AC: 1955 AN: 5172

South Asian (SAS) AF: 0.387 AC: 1866 AN: 4816

European-Finnish (FIN) AF: 0.431 AC: 4546 AN: 10554

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26829 AN: 67978

Other (OTH) AF: 0.403 AC: 851 AN: 2110

Alfa AF: 0.399 Hom.: 54259

Bravo AF: 0.408

Asia WGS AF: 0.372 AC: 1294 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FGFR2-related craniosynostosis Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.19
DANN	Benign	0.74
PhyloP100		-0.44
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: rs1219648; hg19: chr10-123346190;