5-128286782-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001999.4(FBN2):c.6948C>A(p.Ile2316Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,613,916 control chromosomes in the GnomAD database, including 385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I2316I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 21 hom., cov: 33)

Exomes 𝑓: 0.019 ( 364 hom. )

Consequence

FBN2
NM_001999.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.13

Publications

9 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 5-128286782-G-T is Benign according to our data. Variant chr5-128286782-G-T is described in ClinVar as Benign. ClinVar VariationId is 129047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.13 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0149 (2274/152320) while in subpopulation SAS AF = 0.0255 (123/4828). AF 95% confidence interval is 0.0218. There are 21 homozygotes in GnomAd4. There are 1119 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2274 AD gene.

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.6948C>A	p.Ile2316Ile	synonymous	Exon 55 of 65	NP_001990.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBN2	ENST00000262464.9	TSL:1 MANE Select	c.6948C>A	p.Ile2316Ile	synonymous	Exon 55 of 65	ENSP00000262464.4
FBN2	ENST00000939405.1		c.6849C>A	p.Ile2283Ile	synonymous	Exon 54 of 64	ENSP00000609464.1
FBN2	ENST00000939404.1		c.6795C>A	p.Ile2265Ile	synonymous	Exon 54 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes

AF:

0.0149

AC:

2273

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00345

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0252

Gnomad FIN

AF:

0.0211

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0218

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0180

AC:

4521

AN:

251312

AF XY:

0.0192

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00899

Gnomad ASJ exome

AF:

0.0137

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0215

Gnomad NFE exome

AF:

0.0215

Gnomad OTH exome

AF:

0.0238

GnomAD4 exome

AF:

0.0189

AC:

27681

AN:

1461596

Hom.:

364

Cov.:

AF XY:

0.0195

AC XY:

14153

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.00272

AC:

AN:

33470

American (AMR)

AF:

0.00964

AC:

431

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

385

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39690

South Asian (SAS)

AF:

0.0318

AC:

2744

AN:

86252

European-Finnish (FIN)

AF:

0.0226

AC:

1209

AN:

53414

Middle Eastern (MID)

AF:

0.0347

AC:

200

AN:

5766

European-Non Finnish (NFE)

AF:

0.0194

AC:

21530

AN:

1111770

Other (OTH)

AF:

0.0180

AC:

1086

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1516

3033

4549

6066

7582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

748

1496

2244

2992

3740

<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:

0.0149

AC:

2274

AN:

152320

Hom.:

Cov.:

AF XY:

0.0150

AC XY:

1119

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00344

AC:

143

AN:

41570

American (AMR)

AF:

0.0108

AC:

165

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0255

AC:

123

AN:

4828

European-Finnish (FIN)

AF:

0.0211

AC:

224

AN:

10618

Middle Eastern (MID)

AF:

0.0205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0218

AC:

1482

AN:

68024

Other (OTH)

AF:

0.0184

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

113

227

340

454

567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0172

Hom.:

Bravo

AF:

0.0132

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0232

EpiControl

AF:

0.0195

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital contractural arachnodactyly (4)

not specified (4)

not provided (3)

Connective tissue disorder (1)

Ehlers-Danlos syndrome (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.12

(source)

DANN

Benign

0.65

PhyloP100

-1.1

Mutation Taster

=97/3

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