rs28763954

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.976C>T(p.Pro326Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00975 in 1,613,824 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 6 hom., cov: 32)

Exomes 𝑓: 0.010 ( 123 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 4.35

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, 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=0.010052532).

BP6

Variant 5-128408776-G-A is Benign according to our data. Variant chr5-128408776-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00645 (982/152198) while in subpopulation NFE AF = 0.0101 (686/68004). AF 95% confidence interval is 0.00946. There are 6 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 982 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.976C>T	p.Pro326Ser	missense	Exon 8 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.976C>T	p.Pro326Ser	missense	Exon 8 of 65	ENSP00000262464.4	P35556-1
FBN2	ENST00000939405.1		c.877C>T	p.Pro293Ser	missense	Exon 7 of 64	ENSP00000609464.1
FBN2	ENST00000939404.1		c.976C>T	p.Pro326Ser	missense	Exon 8 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes

AF:

0.00646

AC:

983

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.00441

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00189

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00670

AC:

1683

AN:

251020

AF XY:

0.00671

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00492

Gnomad ASJ exome

AF:

0.0134

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00268

Gnomad NFE exome

AF:

0.00982

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.0101

AC:

14757

AN:

1461626

Hom.:

123

Cov.:

AF XY:

0.00992

AC XY:

7213

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33470

American (AMR)

AF:

0.00503

AC:

225

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

347

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00425

AC:

367

AN:

86252

European-Finnish (FIN)

AF:

0.00275

AC:

147

AN:

53418

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0116

AC:

12869

AN:

1111792

Other (OTH)

AF:

0.0113

AC:

683

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

736

1471

2207

2942

3678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

506

1012

1518

2024

2530

<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:

0.00645

AC:

982

AN:

152198

Hom.:

Cov.:

AF XY:

0.00617

AC XY:

459

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41536

American (AMR)

AF:

0.00680

AC:

104

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00373

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00189

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0101

AC:

686

AN:

68004

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

114

172

229

286

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:

0.00936

Hom.:

Bravo

AF:

0.00674

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0120

AC:

103

ExAC

AF:

0.00656

AC:

796

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.0118

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital contractural arachnodactyly (6)

not provided (6)

not specified (3)

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

0.086

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Benign

0.012

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.0025

MutationAssessor

Benign

1.4

PhyloP100

4.3

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.43

Sift

Benign

0.10

Sift4G

Benign

0.085

Polyphen

0.074

Vest4

0.21

MVP

0.61

MPC

0.35

ClinPred

0.031

GERP RS

3.9

Varity_R

0.22

gMVP

0.52

Mutation Taster

=93/7

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