Genetic Variant NM_022970.4:c.696A>G (chr10-121538644-T-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_022970.4(FGFR2):c.696A>G(p.Val232Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 1,613,866 control chromosomes in the GnomAD database, including 488,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V232V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.77 ( 45069 hom., cov: 31)

Exomes 𝑓: 0.78 ( 443218 hom. )

Consequence

FGFR2
NM_022970.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.206

Publications

58 publications found

Variant links:

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: ClinGen, Genomics England PanelApp, G2P, Orphanet
Beare-Stevenson cutis gyrata syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, ClinGen, G2P
bent bone dysplasia syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
Crouzon syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Ambry Genetics, G2P
Jackson-Weiss syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
familial scaphocephaly syndrome, McGillivray type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
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

FGFR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 10-121538644-T-C is Benign according to our data. Variant chr10-121538644-T-C is described in ClinVar as Benign. ClinVar VariationId is 255319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.206 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.886 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGFR2	NM_022970.4	MANE Plus Clinical	c.696A>G	p.Val232Val	synonymous	Exon 6 of 18	NP_075259.4	P21802-3
FGFR2	NM_000141.5	MANE Select	c.696A>G	p.Val232Val	synonymous	Exon 6 of 18	NP_000132.3	P21802-1
FGFR2	NM_001441087.1		c.696A>G	p.Val232Val	synonymous	Exon 6 of 18	NP_001428016.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.696A>G	p.Val232Val	synonymous	Exon 6 of 18	ENSP00000410294.2	P21802-3
FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.696A>G	p.Val232Val	synonymous	Exon 6 of 18	ENSP00000351276.6	P21802-1
FGFR2	ENST00000369056.5	TSL:1	c.696A>G	p.Val232Val	synonymous	Exon 5 of 17	ENSP00000358052.1	P21802-17

Frequencies

GnomAD3 genomes

AF:

0.769

AC:

116849

AN:

151958

Hom.:

45027

Cov.:

show subpopulations

Gnomad AFR

AF:

0.751

Gnomad AMI

AF:

0.779

Gnomad AMR

AF:

0.784

Gnomad ASJ

AF:

0.829

Gnomad EAS

AF:

0.908

Gnomad SAS

AF:

0.744

Gnomad FIN

AF:

0.751

Gnomad MID

AF:

0.825

Gnomad NFE

AF:

0.767

Gnomad OTH

AF:

0.779

GnomAD2 exomes

AF:

0.782

AC:

196571

AN:

251368

AF XY:

0.780

show subpopulations

Gnomad AFR exome

AF:

0.750

Gnomad AMR exome

AF:

0.804

Gnomad ASJ exome

AF:

0.815

Gnomad EAS exome

AF:

0.923

Gnomad FIN exome

AF:

0.755

Gnomad NFE exome

AF:

0.769

Gnomad OTH exome

AF:

0.792

GnomAD4 exome

AF:

0.778

AC:

1136925

AN:

1461792

Hom.:

443218

Cov.:

AF XY:

0.777

AC XY:

564980

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.756

AC:

25306

AN:

33478

American (AMR)

AF:

0.799

AC:

35734

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.819

AC:

21394

AN:

26136

East Asian (EAS)

AF:

0.904

AC:

35877

AN:

39692

South Asian (SAS)

AF:

0.746

AC:

64314

AN:

86254

European-Finnish (FIN)

AF:

0.754

AC:

40253

AN:

53416

Middle Eastern (MID)

AF:

0.824

AC:

4752

AN:

5768

European-Non Finnish (NFE)

AF:

0.775

AC:

861379

AN:

1111934

Other (OTH)

AF:

0.793

AC:

47916

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

15374

30747

46121

61494

76868

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20616

41232

61848

82464

103080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.769

AC:

116950

AN:

152074

Hom.:

45069

Cov.:

AF XY:

0.768

AC XY:

57087

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.752

AC:

31179

AN:

41476

American (AMR)

AF:

0.783

AC:

11970

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.829

AC:

2876

AN:

3470

East Asian (EAS)

AF:

0.908

AC:

4674

AN:

5150

South Asian (SAS)

AF:

0.744

AC:

3588

AN:

4824

European-Finnish (FIN)

AF:

0.751

AC:

7941

AN:

10576

Middle Eastern (MID)

AF:

0.825

AC:

241

AN:

292

European-Non Finnish (NFE)

AF:

0.767

AC:

52128

AN:

67986

Other (OTH)

AF:

0.780

AC:

1643

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1383

2766

4150

5533

6916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

864

1728

2592

3456

4320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.771

Hom.:

99508

Bravo

AF:

0.775

Asia WGS

AF:

0.808

AC:

2809

AN:

3478

EpiCase

AF:

0.779

EpiControl

AF:

0.788

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Beare-Stevenson cutis gyrata syndrome (1)

Craniosynostosis syndrome (1)

Crouzon syndrome (1)

FGFR2-related craniosynostosis (1)

Isolated Coronal Synostosis (1)

not provided (1)

Saethre-Chotzen syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.21

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over