rs757028268

Positions:

chr5-128259750-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The ENST00000262464.9(FBN2):c.8444A>C(p.Lys2815Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

FBN2
ENST00000262464.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 0.325

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 Likely_benign. Variant got -5 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.33476314).

BP6

Variant 5-128259750-T-G is Benign according to our data. Variant chr5-128259750-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 528397.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.8444A>C	p.Lys2815Thr	missense_variant	65/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3 linkuse as main transcript	c.8291A>C	p.Lys2764Thr	missense_variant	64/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.8444A>C	p.Lys2815Thr	missense_variant	65/65	1	NM_001999.4	ENSP00000262464	P1	P35556-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151940

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:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251136

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135712

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727218

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:

0.00

Gnomad4 NFE exome

AF:

0.0000603

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151940

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74206

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:

0.0000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2023	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 06, 2022	The FBN2 c.8444A>C; p.Lys2815Thr variant (rs757028268), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 528397). This variant is found in the general population with an overall allele frequency of 0.002% (5/282524 alleles) in the Genome Aggregation Database. The lysine at codon 2815 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.506). Due to limited information, the clinical significance of this variant is uncertain at this time. -

FBN2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2024

The FBN2 c.8444A>C variant is predicted to result in the amino acid substitution p.Lys2815Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2018

The p.K2815T variant (also known as c.8444A>C), located in coding exon 65 of the FBN2 gene, results from an A to C substitution at nucleotide position 8444. The lysine at codon 2815 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 20, 2024

Variant summary: FBN2 c.8444A>C (p.Lys2815Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 1613780 control chromosomes. The observed variant frequency is approximately 36.68 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN2 causing Aortopathy phenotype (1.3e-06). c.8444A>C has been reported in the literature in an individual affected with Spontaneous Coronary Artery Dissection, without strong evidence for causality (Tarr_2022). This report does not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35583931). ClinVar contains an entry for this variant (Variation ID: 528397). Based on the evidence outlined above, the variant was classified as likely benign. -

Congenital contractural arachnodactyly

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

D;.;D

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.24

T;.;.

M_CAP

Benign

0.065

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.6

M;.;M

MutationTaster

Benign

0.78

D;D

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.2

D;.;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.014

D;.;D

Polyphen

0.079

B;.;B

Vest4

0.45

MVP

0.76

MPC

0.31

ClinPred

0.33

GERP RS

4.3

Varity_R

0.14

gMVP

0.56

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