rs34450503

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.1592G>C(p.Gly531Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000995 in 1,613,724 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G531G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 9 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.55

Publications

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

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=0.009535283).

BP6

Variant 5-128392029-C-G is Benign according to our data. Variant chr5-128392029-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00116 (177/152310) while in subpopulation SAS AF = 0.00207 (10/4830). AF 95% confidence interval is 0.00149. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 177 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.1592G>C	p.Gly531Ala	missense	Exon 11 of 65	NP_001990.2	P35556-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBN2	ENST00000262464.9	TSL:1 MANE Select	c.1592G>C	p.Gly531Ala	missense	Exon 11 of 65	ENSP00000262464.4	P35556-1
FBN2	ENST00000939405.1		c.1493G>C	p.Gly498Ala	missense	Exon 10 of 64	ENSP00000609464.1
FBN2	ENST00000939404.1		c.1439G>C	p.Gly480Ala	missense	Exon 10 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

177

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00175

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00136

AC:

342

AN:

251046

AF XY:

0.00148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00636

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00217

Gnomad NFE exome

AF:

0.00155

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.000978

AC:

1429

AN:

1461414

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

771

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.000134

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00635

AC:

166

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00154

AC:

133

AN:

86244

European-Finnish (FIN)

AF:

0.00213

AC:

114

AN:

53402

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000865

AC:

962

AN:

1111700

Other (OTH)

AF:

0.000729

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

138

208

277

346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00116

AC:

177

AN:

152310

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00175

AC:

119

AN:

68008

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00178

Hom.:

Bravo

AF:

0.000854

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00128

AC:

155

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00119

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 (3)

Congenital contractural arachnodactyly (2)

Connective tissue disorder (1)

Ehlers-Danlos syndrome (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

FBN2-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.071

MetaRNN

Benign

0.0095

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.2

PhyloP100

4.5

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.62

Sift

Uncertain

0.011

Sift4G

Benign

0.11

Polyphen

0.96

Vest4

0.33

MVP

0.80

MPC

0.34

ClinPred

0.12

GERP RS

4.1

Varity_R

0.47

gMVP

0.72

Mutation Taster

=55/45

polymorphism

(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