NM_001999.4:c.1897A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP6

The NM_001999.4(FBN2):c.1897A>G(p.Ile633Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,326 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 1 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.18

Publications

1 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 5-128376806-T-C is Benign according to our data. Variant chr5-128376806-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547353.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.1897A>G	p.Ile633Val	missense_variant	Exon 14 of 65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.1744A>G	p.Ile582Val	missense_variant	Exon 13 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBN2	ENST00000262464.9 link	c.1897A>G	p.Ile633Val	missense_variant	Exon 14 of 65	1	NM_001999.4	ENSP00000262464.4	P35556-1
FBN2	ENST00000508989.5 link	c.1798A>G	p.Ile600Val	missense_variant	Exon 13 of 33	2		ENSP00000425596.1	D6RJI3
FBN2	ENST00000511489.1 link	n.118A>G		non_coding_transcript_exon_variant	Exon 2 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251072

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461326

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726974

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.0000895

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111644

Other (OTH)

AF:

0.00

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Connective tissue disorder

Uncertain:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital contractural arachnodactyly

Benign:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;.;T;T

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.78

T;.;.;T

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

-0.17

N;.;N;.

PhyloP100

6.2

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.67

N;.;N;N

REVEL

Uncertain

0.55

Sift

Benign

0.36

T;.;T;T

Sift4G

Benign

0.34

.;.;.;T

Polyphen

0.90

P;.;P;P

Vest4

0.59

MutPred

0.51

Gain of catalytic residue at I633 (P = 0.0767);.;Gain of catalytic residue at I633 (P = 0.0767);.;

MVP

0.79

MPC

0.26

ClinPred

0.59

GERP RS

4.6

Varity_R

0.11

gMVP

0.65

Mutation Taster

=44/56

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over