NM_001999.4:c.6880+17G>A

Variant names:

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.6880+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,612,308 control chromosomes in the GnomAD database, including 247,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 18921 hom., cov: 32)

Exomes 𝑓: 0.55 ( 228610 hom. )

Consequence

FBN2
NM_001999.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.804

Publications

16 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=-0.83).

BP6

Variant 5-128287291-C-T is Benign according to our data. Variant chr5-128287291-C-T is described in ClinVar as Benign. ClinVar VariationId is 137347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.6880+17G>A		intron_variant	Intron 54 of 64	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.6727+17G>A		intron_variant	Intron 53 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 link	c.6880+17G>A		intron_variant	Intron 54 of 64	1	NM_001999.4	ENSP00000262464.4		P35556-1
FBN2	ENST00000703783.1 link	n.3664+17G>A		intron_variant	Intron 29 of 37

Frequencies

GnomAD3 genomes

AF:

0.458

AC:

69575

AN:

151958

Hom.:

18911

Cov.:

show subpopulations

Gnomad AFR

AF:

0.164

Gnomad AMI

AF:

0.582

Gnomad AMR

AF:

0.555

Gnomad ASJ

AF:

0.552

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.506

Gnomad FIN

AF:

0.693

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.586

Gnomad OTH

AF:

0.488

GnomAD2 exomes

AF:

0.523

AC:

131520

AN:

251234

AF XY:

0.533

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.557

Gnomad ASJ exome

AF:

0.545

Gnomad EAS exome

AF:

0.186

Gnomad FIN exome

AF:

0.682

Gnomad NFE exome

AF:

0.587

Gnomad OTH exome

AF:

0.574

GnomAD4 exome

AF:

0.551

AC:

804264

AN:

1460230

Hom.:

228610

Cov.:

AF XY:

0.552

AC XY:

401282

AN XY:

726490

show subpopulations

African (AFR)

AF:

0.150

AC:

5011

AN:

33432

American (AMR)

AF:

0.557

AC:

24890

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.552

AC:

14415

AN:

26112

East Asian (EAS)

AF:

0.208

AC:

8246

AN:

39660

South Asian (SAS)

AF:

0.520

AC:

44826

AN:

86186

European-Finnish (FIN)

AF:

0.686

AC:

36574

AN:

53348

Middle Eastern (MID)

AF:

0.562

AC:

3241

AN:

5762

European-Non Finnish (NFE)

AF:

0.572

AC:

635862

AN:

1110700

Other (OTH)

AF:

0.517

AC:

31199

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

16834

33667

50501

67334

84168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17208

34416

51624

68832

86040

<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:

0.458

AC:

69588

AN:

152078

Hom.:

18921

Cov.:

AF XY:

0.463

AC XY:

34382

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.164

AC:

6803

AN:

41470

American (AMR)

AF:

0.555

AC:

8487

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.552

AC:

1915

AN:

3470

East Asian (EAS)

AF:

0.201

AC:

1040

AN:

5172

South Asian (SAS)

AF:

0.507

AC:

2444

AN:

4816

European-Finnish (FIN)

AF:

0.693

AC:

7313

AN:

10560

Middle Eastern (MID)

AF:

0.578

AC:

170

AN:

294

European-Non Finnish (NFE)

AF:

0.586

AC:

39856

AN:

67986

Other (OTH)

AF:

0.487

AC:

1029

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1662

3324

4985

6647

8309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

618

1236

1854

2472

3090

<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:

0.541

Hom.:

16380

Bravo

AF:

0.427

Asia WGS

AF:

0.391

AC:

1359

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital contractural arachnodactyly

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Nov 02, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The FBN2 c.6880+17G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been observed in a large, broad control population, ExAC, in 62933/121394 control chromosomes at a frequency of 0.5184194, which is approximately 414735 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), strong evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories databases classified this variant as benign. Taken together, this variant is classified as benign. -

Macular degeneration, early-onset

Benign:1

Aug 10, 2021

Genome-Nilou Lab

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

-0.83

CADD

Benign

0.81

(source)

DANN

Benign

0.43

PhyloP100

-0.80

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over