chr5-128464822-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001999.4(FBN2):c.728T>C(p.Ile243Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00796 in 1,614,250 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 89 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 7.46

Publications

12 publications found

Variant links:

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

FBN2 Gene-Disease associations (from GenCC):

congenital contractural arachnodactyly
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
carpal tunnel syndrome
Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
macular degeneration, early-onset
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

FBN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01372388).

BP6

Variant 5-128464822-A-G is Benign according to our data. Variant chr5-128464822-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00732 (1116/152358) while in subpopulation EAS AF = 0.0489 (253/5176). AF 95% confidence interval is 0.0439. There are 11 homozygotes in GnomAd4. There are 588 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1116 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001999.4. 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
	FBN2	NM_001999.4	MANE Select	c.728T>C	p.Ile243Thr	missense	Exon 6 of 65	NP_001990.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBN2	ENST00000262464.9	TSL:1 MANE Select	c.728T>C	p.Ile243Thr	missense	Exon 6 of 65	ENSP00000262464.4
FBN2	ENST00000502468.5	TSL:1	c.728T>C	p.Ile243Thr	missense	Exon 6 of 8	ENSP00000424753.1
FBN2	ENST00000508989.5	TSL:2	c.629T>C	p.Ile210Thr	missense	Exon 5 of 33	ENSP00000425596.1

Frequencies

GnomAD3 genomes

AF:

0.00736

AC:

1121

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.0492

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0197

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00679

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00973

AC:

2446

AN:

251408

AF XY:

0.00962

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.0453

Gnomad FIN exome

AF:

0.0213

Gnomad NFE exome

AF:

0.00710

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.00803

AC:

11732

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00786

AC XY:

5719

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

33480

American (AMR)

AF:

0.00253

AC:

113

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00539

AC:

141

AN:

26136

East Asian (EAS)

AF:

0.0336

AC:

1332

AN:

39700

South Asian (SAS)

AF:

0.00417

AC:

360

AN:

86258

European-Finnish (FIN)

AF:

0.0218

AC:

1165

AN:

53420

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00714

AC:

7940

AN:

1112012

Other (OTH)

AF:

0.0102

AC:

617

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

786

1572

2358

3144

3930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

322

644

966

1288

1610

<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:

0.00732

AC:

1116

AN:

152358

Hom.:

Cov.:

AF XY:

0.00789

AC XY:

588

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41602

American (AMR)

AF:

0.00366

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3470

East Asian (EAS)

AF:

0.0489

AC:

253

AN:

5176

South Asian (SAS)

AF:

0.00601

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0197

AC:

209

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00679

AC:

462

AN:

68026

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00775

Hom.:

Bravo

AF:

0.00655

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00947

AC:

1150

Asia WGS

AF:

0.0300

AC:

105

AN:

3478

EpiCase

AF:

0.00643

EpiControl

AF:

0.00593

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (3)

Congenital contractural arachnodactyly (2)

Connective tissue disorder (2)

Ehlers-Danlos syndrome (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Benign

0.054

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.45

MetaRNN

Benign

0.014

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

1.3

PhyloP100

7.5

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.57

Sift

Uncertain

0.029

Sift4G

Uncertain

0.0030

Polyphen

0.64

Vest4

0.51

MVP

0.62

MPC

0.82

ClinPred

0.039

GERP RS

3.6

Varity_R

0.14

gMVP

0.32

Mutation Taster

=38/62

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over