Genetic Variant FBN2:c.3343+35T>A (chr5-128344350-A-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.3343+35T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0985 in 1,611,170 control chromosomes in the GnomAD database, including 8,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.076 ( 639 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8351 hom. )

Consequence

FBN2
NM_001999.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0420

Publications

5 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=-0.84).

BP6

Variant 5-128344350-A-T is Benign according to our data. Variant chr5-128344350-A-T is described in ClinVar as Benign. ClinVar VariationId is 258516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.3343+35T>A		intron_variant	Intron 25 of 64	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.3190+35T>A		intron_variant	Intron 24 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 link	c.3343+35T>A		intron_variant	Intron 25 of 64	1	NM_001999.4	ENSP00000262464.4		P35556-1
FBN2	ENST00000508989.5 link	c.3244+35T>A		intron_variant	Intron 24 of 32	2		ENSP00000425596.1		D6RJI3

Frequencies

GnomAD3 genomes

AF:

0.0757

AC:

11525

AN:

152204

Hom.:

639

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0206

Gnomad AMI

AF:

0.125

Gnomad AMR

AF:

0.0830

Gnomad ASJ

AF:

0.0568

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0304

Gnomad FIN

AF:

0.0695

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.0660

GnomAD2 exomes

AF:

0.0772

AC:

19405

AN:

251286

AF XY:

0.0787

show subpopulations

Gnomad AFR exome

AF:

0.0195

Gnomad AMR exome

AF:

0.0478

Gnomad ASJ exome

AF:

0.0546

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0749

Gnomad NFE exome

AF:

0.120

Gnomad OTH exome

AF:

0.0917

GnomAD4 exome

AF:

0.101

AC:

147155

AN:

1458848

Hom.:

8351

Cov.:

AF XY:

0.0991

AC XY:

71959

AN XY:

725896

show subpopulations

African (AFR)

AF:

0.0166

AC:

556

AN:

33428

American (AMR)

AF:

0.0508

AC:

2272

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0557

AC:

1454

AN:

26104

East Asian (EAS)

AF:

0.000101

AC:

AN:

39670

South Asian (SAS)

AF:

0.0373

AC:

3217

AN:

86232

European-Finnish (FIN)

AF:

0.0789

AC:

4214

AN:

53402

Middle Eastern (MID)

AF:

0.0515

AC:

297

AN:

5764

European-Non Finnish (NFE)

AF:

0.117

AC:

130051

AN:

1109226

Other (OTH)

AF:

0.0844

AC:

5090

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

6454

12907

19361

25814

32268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4460

8920

13380

17840

22300

<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:

0.0756

AC:

11523

AN:

152322

Hom.:

639

Cov.:

AF XY:

0.0716

AC XY:

5332

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0205

AC:

854

AN:

41576

American (AMR)

AF:

0.0829

AC:

1269

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0568

AC:

197

AN:

3468

East Asian (EAS)

AF:

0.000770

AC:

AN:

5192

South Asian (SAS)

AF:

0.0296

AC:

143

AN:

4828

European-Finnish (FIN)

AF:

0.0695

AC:

739

AN:

10626

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8054

AN:

68012

Other (OTH)

AF:

0.0653

AC:

138

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

542

1083

1625

2166

2708

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:

0.0909

Hom.:

145

Bravo

AF:

0.0730

Asia WGS

AF:

0.0170

AC:

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

-0.84

CADD

Benign

3.3

(source)

DANN

Benign

0.72

PhyloP100

0.042

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

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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