Variant chr5-128374681-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PP2PP3_ModerateBP6_ModerateBS2

The NM_001999.4(FBN2):c.2042G>T(p.Arg681Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R681H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.15

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 links:

FBN2 (HGNC:):

FBN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

BP6

Variant 5-128374681-C-A is Benign according to our data. Variant chr5-128374681-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1469986.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.2042G>T	p.Arg681Leu	missense_variant	15/65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 linkuse as main transcript	c.1889G>T	p.Arg630Leu	missense_variant	14/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.2042G>T	p.Arg681Leu	missense_variant	15/65	1	NM_001999.4	ENSP00000262464.4	P35556-1
FBN2	ENST00000508989.5 linkuse as main transcript	c.1943G>T	p.Arg648Leu	missense_variant	14/33	2		ENSP00000425596.1	D6RJI3
FBN2	ENST00000511489.1 linkuse as main transcript	n.263G>T		non_coding_transcript_exon_variant	3/6	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250920

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135586

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital contractural arachnodactyly

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;.;D;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

T;.;.;T

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.5

L;.;L;.

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.8

D;.;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0020

D;.;D;D

Sift4G

Benign

0.28

.;.;.;T

Polyphen

0.98

D;.;D;D

Vest4

0.79

MutPred

0.65

Loss of disorder (P = 0.0703);.;Loss of disorder (P = 0.0703);.;

MVP

0.96

MPC

0.43

ClinPred

0.85

GERP RS

4.5

Varity_R

0.67

gMVP

0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over