Genetic Variant FBLN2:p.Arg80Cys (chr3-13570593-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001004019.2(FBLN2):c.238C>T(p.Arg80Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000824 in 1,578,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

FBLN2
NM_001004019.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.73

Publications

1 publications found

Variant links:

Genes affected

FBLN2 (HGNC:3601): (fibulin 2) This gene encodes an extracellular matrix protein, which belongs to the fibulin family. This protein binds various extracellular ligands and calcium. It may play a role during organ development, in particular, during the differentiation of heart, skeletal and neuronal structures. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

FBLN2 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
pulmonary arterial hypertension
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

FBLN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18657151).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004019.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBLN2	NM_001004019.2	MANE Select	c.238C>T	p.Arg80Cys	missense	Exon 2 of 18	NP_001004019.1	P98095-2
FBLN2	NM_001165035.2		c.238C>T	p.Arg80Cys	missense	Exon 2 of 18	NP_001158507.1	P98095-2
FBLN2	NM_001998.3		c.238C>T	p.Arg80Cys	missense	Exon 2 of 17	NP_001989.2	P98095-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBLN2	ENST00000404922.8	TSL:5 MANE Select	c.238C>T	p.Arg80Cys	missense	Exon 2 of 18	ENSP00000384169.3	P98095-2
FBLN2	ENST00000295760.11	TSL:1	c.238C>T	p.Arg80Cys	missense	Exon 2 of 17	ENSP00000295760.7	P98095-1
FBLN2	ENST00000492059.5	TSL:2	c.238C>T	p.Arg80Cys	missense	Exon 2 of 18	ENSP00000420042.1	P98095-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000218

AC:

AN:

183442

AF XY:

0.0000200

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000114

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000771

AC:

AN:

1426264

Hom.:

Cov.:

AF XY:

0.00000849

AC XY:

AN XY:

706502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32810

American (AMR)

AF:

0.00

AC:

AN:

39806

Ashkenazi Jewish (ASJ)

AF:

0.0000392

AC:

AN:

25494

East Asian (EAS)

AF:

0.0000264

AC:

AN:

37876

South Asian (SAS)

AF:

0.0000245

AC:

AN:

81620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000639

AC:

AN:

1095268

Other (OTH)

AF:

0.00

AC:

AN:

59040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000842

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.018

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

PhyloP100

2.7

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

REVEL

Benign

0.17

Sift

Uncertain

0.025

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.43

MVP

0.30

MPC

0.59

ClinPred

0.52

GERP RS

1.9

Varity_R

0.066

gMVP

0.39

Mutation Taster

=89/11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over