chr5-128289088-T-C

Variant names:

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.6637+39A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0334 in 1,610,364 control chromosomes in the GnomAD database, including 1,078 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 83 hom., cov: 32)

Exomes 𝑓: 0.034 ( 995 hom. )

Consequence

FBN2
NM_001999.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -5.38

Publications

3 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 5-128289088-T-C is Benign according to our data. Variant chr5-128289088-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0281 (4278/152246) while in subpopulation AMR AF = 0.0415 (634/15280). AF 95% confidence interval is 0.0392. There are 83 homozygotes in GnomAd4. There are 2038 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4278 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.6637+39A>G		intron_variant	Intron 52 of 64	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.6484+39A>G		intron_variant	Intron 51 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBN2	ENST00000262464.9 link	c.6637+39A>G	intron_variant	Intron 52 of 64	1	NM_001999.4	ENSP00000262464.4	P35556-1
FBN2	ENST00000703783.1 link	n.3421+39A>G	intron_variant	Intron 27 of 37
FBN2	ENST00000703785.1 link	n.3340+39A>G	intron_variant	Intron 26 of 26

Frequencies

GnomAD3 genomes

AF:

0.0281

AC:

4279

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00765

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0415

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00662

Gnomad FIN

AF:

0.0397

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0405

Gnomad OTH

AF:

0.0292

GnomAD2 exomes

AF:

0.0278

AC:

6948

AN:

249988

AF XY:

0.0281

show subpopulations

Gnomad AFR exome

AF:

0.00663

Gnomad AMR exome

AF:

0.0214

Gnomad ASJ exome

AF:

0.00858

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0425

Gnomad NFE exome

AF:

0.0412

Gnomad OTH exome

AF:

0.0378

GnomAD4 exome

AF:

0.0339

AC:

49491

AN:

1458118

Hom.:

995

Cov.:

AF XY:

0.0333

AC XY:

24201

AN XY:

725682

show subpopulations

African (AFR)

AF:

0.00587

AC:

196

AN:

33404

American (AMR)

AF:

0.0232

AC:

1038

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00796

AC:

208

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00746

AC:

643

AN:

86208

European-Finnish (FIN)

AF:

0.0447

AC:

2385

AN:

53326

Middle Eastern (MID)

AF:

0.0203

AC:

117

AN:

5752

European-Non Finnish (NFE)

AF:

0.0389

AC:

43129

AN:

1108688

Other (OTH)

AF:

0.0295

AC:

1775

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

2394

4788

7183

9577

11971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1538

3076

4614

6152

7690

<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:

0.0281

AC:

4278

AN:

152246

Hom.:

Cov.:

AF XY:

0.0274

AC XY:

2038

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00763

AC:

317

AN:

41552

American (AMR)

AF:

0.0415

AC:

634

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00663

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0397

AC:

421

AN:

10604

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0405

AC:

2752

AN:

68016

Other (OTH)

AF:

0.0289

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

208

415

623

830

1038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0281

Hom.:

Bravo

AF:

0.0259

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 14, 2018

GeneDx

Significance:Likely 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. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

0.0030

(source)

DANN

Benign

0.65

PhyloP100

-5.4

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