10-121485320-C-T

Variant names:

• chr10-121485320-C-T
• rs1613776
• NM_022970.4:c.2198+75G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022970.4(FGFR2):​c.2198+75G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0488 in 1,598,834 control chromosomes in the GnomAD database, including 2,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (774 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1938 hom.)
• Consequence: FGFR2 NM_022970.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.854
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-121485320-C-T is Benign according to our data. Variant chr10-121485320-C-T is described in ClinVar as Benign. ClinVar VariationId is 1222606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	NM_022970.4	MANE Plus Clinical	c.2198+75G>A		intron	N/A	NP_075259.4
	FGFR2	NM_000141.5	MANE Select	c.2195+75G>A		intron	N/A	NP_000132.3
	FGFR2	NM_001441087.1		c.2192+75G>A		intron	N/A	NP_001428016.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.2198+75G>A		intron	N/A	ENSP00000410294.2
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.2195+75G>A		intron	N/A	ENSP00000351276.6
	FGFR2	ENST00000369056.5	TSL:1	c.2198+75G>A		intron	N/A	ENSP00000358052.1

Frequencies

GnomAD3 genomes AF: 0.0791 AC: 12020 AN: 152010 Hom.: 770 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0385

Gnomad ASJ AF: 0.0567

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0608

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0592

GnomAD4 exome AF: 0.0456 AC: 65939 AN: 1446706 Hom.: 1938 AF XY: 0.0444 AC XY: 31991 AN XY: 720536

African (AFR) AF: 0.179 AC: 5922 AN: 33174

American (AMR) AF: 0.0339 AC: 1516 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 1683 AN: 26056

East Asian (EAS) AF: 0.00916 AC: 363 AN: 39616

South Asian (SAS) AF: 0.0177 AC: 1521 AN: 85706

European-Finnish (FIN) AF: 0.0634 AC: 3382 AN: 53310

Middle Eastern (MID) AF: 0.0533 AC: 270 AN: 5066

European-Non Finnish (NFE) AF: 0.0438 AC: 48142 AN: 1099282

Other (OTH) AF: 0.0525 AC: 3140 AN: 59822

GnomAD4 genome AF: 0.0792 AC: 12050 AN: 152128 Hom.: 774 Cov.: 32 AF XY: 0.0776 AC XY: 5773 AN XY: 74374

African (AFR) AF: 0.176 AC: 7298 AN: 41468

American (AMR) AF: 0.0384 AC: 587 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0567 AC: 197 AN: 3472

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5170

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4808

European-Finnish (FIN) AF: 0.0608 AC: 644 AN: 10598

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0443 AC: 3012 AN: 68012

Other (OTH) AF: 0.0595 AC: 126 AN: 2116

Alfa AF: 0.0484 Hom.: 522

Bravo AF: 0.0823

Asia WGS AF: 0.0390 AC: 137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.71
DANN	Benign	0.47
PhyloP100		-0.85
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: rs1613776; hg19: chr10-123244834;