Genetic Variant FBN2:c.2429-48T>C (chr5-128361896-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001999.4(FBN2):c.2429-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0865 in 1,576,632 control chromosomes in the GnomAD database, including 6,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 448 hom., cov: 32)

Exomes 𝑓: 0.089 ( 5946 hom. )

Consequence

FBN2
NM_001999.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0880

Publications

7 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 (BayesDel_noAF=-0.88).

BP6

Variant 5-128361896-A-G is Benign according to our data. Variant chr5-128361896-A-G is described in ClinVar as Benign. ClinVar VariationId is 258512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0934 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.2429-48T>C		intron_variant	Intron 18 of 64	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.2276-48T>C		intron_variant	Intron 17 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 link	c.2429-48T>C		intron_variant	Intron 18 of 64	1	NM_001999.4	ENSP00000262464.4		P35556-1
FBN2	ENST00000508989.5 link	c.2330-48T>C		intron_variant	Intron 17 of 32	2		ENSP00000425596.1		D6RJI3

Frequencies

GnomAD3 genomes

AF:

0.0680

AC:

10349

AN:

152150

Hom.:

449

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0226

Gnomad AMI

AF:

0.203

Gnomad AMR

AF:

0.0540

Gnomad ASJ

AF:

0.0493

Gnomad EAS

AF:

0.0643

Gnomad SAS

AF:

0.0494

Gnomad FIN

AF:

0.0944

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0954

Gnomad OTH

AF:

0.0679

GnomAD2 exomes

AF:

0.0729

AC:

18325

AN:

251232

AF XY:

0.0736

show subpopulations

Gnomad AFR exome

AF:

0.0230

Gnomad AMR exome

AF:

0.0416

Gnomad ASJ exome

AF:

0.0454

Gnomad EAS exome

AF:

0.0582

Gnomad FIN exome

AF:

0.0954

Gnomad NFE exome

AF:

0.0976

Gnomad OTH exome

AF:

0.0753

GnomAD4 exome

AF:

0.0885

AC:

126077

AN:

1424364

Hom.:

5946

Cov.:

AF XY:

0.0871

AC XY:

61932

AN XY:

711044

show subpopulations

African (AFR)

AF:

0.0238

AC:

780

AN:

32738

American (AMR)

AF:

0.0434

AC:

1940

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

1168

AN:

25862

East Asian (EAS)

AF:

0.0508

AC:

2004

AN:

39472

South Asian (SAS)

AF:

0.0456

AC:

3895

AN:

85488

European-Finnish (FIN)

AF:

0.0954

AC:

5079

AN:

53234

Middle Eastern (MID)

AF:

0.0814

AC:

463

AN:

5688

European-Non Finnish (NFE)

AF:

0.0981

AC:

105800

AN:

1078158

Other (OTH)

AF:

0.0838

AC:

4948

AN:

59040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

5634

11268

16902

22536

28170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3754

7508

11262

15016

18770

<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:

0.0679

AC:

10344

AN:

152268

Hom.:

448

Cov.:

AF XY:

0.0663

AC XY:

4935

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0226

AC:

940

AN:

41568

American (AMR)

AF:

0.0539

AC:

824

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0493

AC:

171

AN:

3468

East Asian (EAS)

AF:

0.0642

AC:

333

AN:

5184

South Asian (SAS)

AF:

0.0488

AC:

235

AN:

4818

European-Finnish (FIN)

AF:

0.0944

AC:

1001

AN:

10602

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0953

AC:

6485

AN:

68018

Other (OTH)

AF:

0.0676

AC:

143

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

496

992

1489

1985

2481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0850

Hom.:

470

Bravo

AF:

0.0644

Asia WGS

AF:

0.0640

AC:

221

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.39

(source)

DANN

Benign

0.31

PhyloP100

0.088

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over