rs141707850

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_001999.4(FBN2):c.6334A>G(p.Lys2112Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2112R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.77

Publications

6 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33632803).

BP6

Variant 5-128290843-T-C is Benign according to our data. Variant chr5-128290843-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213419.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000205 (300/1461784) while in subpopulation NFE AF = 0.000239 (266/1111928). AF 95% confidence interval is 0.000215. There are 0 homozygotes in GnomAdExome4. There are 137 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.6334A>G	p.Lys2112Glu	missense_variant	Exon 50 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3 link	c.6181A>G	p.Lys2061Glu	missense_variant	Exon 49 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FBN2	ENST00000262464.9 link	c.6334A>G	p.Lys2112Glu	missense_variant	Exon 50 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1 link	n.3118A>G		non_coding_transcript_exon_variant	Exon 25 of 38
FBN2	ENST00000703785.1 link	n.3037A>G		non_coding_transcript_exon_variant	Exon 24 of 27

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000143

AC:

AN:

251214

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000205

AC:

300

AN:

1461784

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

137

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000239

AC:

266

AN:

1111928

Other (OTH)

AF:

0.000149

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000118

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41558

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000170

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

May 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.K2112E variant (also known as c.6334A>G), located in coding exon 50 of the FBN2 gene, results from an A to G substitution at nucleotide position 6334. The lysine at codon 2112 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Sep 04, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Congenital contractural arachnodactyly

Benign:1

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.93

D;.;.

M_CAP

Benign

0.079

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.5

L;.;L

PhyloP100

2.8

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.3

N;.;N

REVEL

Pathogenic

0.73

Sift

Benign

0.088

T;.;T

Polyphen

0.91

P;.;P

Vest4

0.50

MVP

0.99

MPC

0.96

ClinPred

0.24

GERP RS

5.0

Varity_R

0.23

gMVP

0.62

Mutation Taster

=61/39

polymorphism

(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