5-128280272-C-T

Position:

chr5-128280272-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2

The NM_001999.4(FBN2):c.7058G>A(p.Arg2353His) variant causes a missense change. The variant allele was found at a frequency of 0.00000931 in 1,611,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.54

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 -4 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.

BP6

Variant 5-128280272-C-T is Benign according to our data. Variant chr5-128280272-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411818.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.7058G>A	p.Arg2353His	missense_variant	56/65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 linkuse as main transcript	c.6905G>A	p.Arg2302His	missense_variant	55/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.7058G>A	p.Arg2353His	missense_variant	56/65	1	NM_001999.4	ENSP00000262464.4		P35556-1
FBN2	ENST00000703783.1 linkuse as main transcript	n.3842G>A		non_coding_transcript_exon_variant	31/38

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250820

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135530

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:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000960

AC:

AN:

1458818

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

725884

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 26, 2019

The FBN2 c.7058G>A; p.Arg2353His variant (rs775905979), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 411818). This variant is only observed on 3 out of 250,820 allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 2353 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Arg2353His variant is uncertain at this time. -

Congenital contractural arachnodactyly

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.;D

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;.;.

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Uncertain

-0.039

MutationAssessor

Benign

1.4

L;.;L

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.3

N;.;N

REVEL

Pathogenic

0.66

Sift

Benign

0.15

T;.;T

Polyphen

0.74

P;.;P

Vest4

0.27

MutPred

0.67

Loss of disorder (P = 0.0716);.;Loss of disorder (P = 0.0716);

MVP

0.97

MPC

0.38

ClinPred

0.78

GERP RS

4.1

Varity_R

0.089

gMVP

0.73

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