Variant rs146997253 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM1PP2BP4_StrongBP6_ModerateBS2

The NM_001999.4(FBN2):c.3595G>A(p.Val1199Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,614,104 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. V1199V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00046 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.16

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_001999.4

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.02257669).

BP6

Variant 5-128338000-C-T is Benign according to our data. Variant chr5-128338000-C-T is described in ClinVar as [Benign]. Clinvar id is 528433.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.3595G>A	p.Val1199Met	missense_variant	27/65	ENST00000262464.9
FBN2	XM_017009228.3 linkuse as main transcript	c.3442G>A	p.Val1148Met	missense_variant	26/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.3595G>A	p.Val1199Met	missense_variant	27/65	1	NM_001999.4	P1	P35556-1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152226

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:

0.00631

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000537

AC:

135

AN:

251356

Hom.:

AF XY:

0.000574

AC XY:

AN XY:

135872

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:

0.00

Gnomad FIN exome

AF:

0.00554

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000218

AC:

318

AN:

1461760

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

166

AN XY:

727192

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:

0.00

Gnomad4 FIN exome

AF:

0.00530

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000459

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74492

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:

0.00631

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000541

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000412

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital contractural arachnodactyly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

T;.;T;T;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

D;.;.;D;D

M_CAP

Benign

0.069

MetaRNN

Benign

0.023

T;T;T;T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.0

M;.;M;.;.

MutationTaster

Benign

0.67

D;D;D;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.80

N;.;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.13

T;.;T;T;T

Sift4G

Benign

0.11

.;.;.;T;T

Polyphen

0.23

B;.;B;.;P

Vest4

0.25

MVP

0.82

MPC

0.25

ClinPred

0.13

GERP RS

4.1

Varity_R

0.081

gMVP

0.48

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