dbSNP rs2042327: FBN2:c.6880+17G>A (chr5-128287291-C-T) – 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.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: 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 (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.

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.6880+17G>A		intron	N/A	NP_001990.2	P35556-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FBN2	ENST00000262464.9	TSL:1 MANE Select	c.6880+17G>A	intron	N/A	ENSP00000262464.4	P35556-1
FBN2	ENST00000939405.1		c.6781+17G>A	intron	N/A	ENSP00000609464.1
FBN2	ENST00000939404.1		c.6727+17G>A	intron	N/A	ENSP00000609463.1

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital contractural arachnodactyly (4)

not provided (2)

not specified (2)

Macular degeneration, early-onset (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over