rs78727187

Positions:

chr5-128332993-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_001999.4(FBN2):c.4141C>A(p.His1381Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00512 in 1,608,724 control chromosomes in the GnomAD database, including 24 homozygotes. 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 0.0032 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 23 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: 5.62

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 -10 ACMG points.

PM1

In a domain EGF-like 22; calcium-binding (size 40) in uniprot entity FBN2_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) 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=0.012713194).

BP6

Variant 5-128332993-G-T is Benign according to our data. Variant chr5-128332993-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210996.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=7, Uncertain_significance=1}. Variant chr5-128332993-G-T is described in Lovd as [Likely_benign]. Variant chr5-128332993-G-T is described in Lovd as [Benign]. Variant chr5-128332993-G-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00323 (492/152278) while in subpopulation NFE AF= 0.00529 (360/68032). AF 95% confidence interval is 0.00484. There are 1 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 492 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.4141C>A	p.His1381Asn	missense_variant	32/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3 linkuse as main transcript	c.3988C>A	p.His1330Asn	missense_variant	31/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.4141C>A	p.His1381Asn	missense_variant	32/65	1	NM_001999.4	ENSP00000262464	P1	P35556-1

Frequencies

GnomAD3 genomes

AF:

0.00323

AC:

492

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00529

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00372

AC:

934

AN:

251292

Hom.:

AF XY:

0.00360

AC XY:

489

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00675

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00154

Gnomad FIN exome

AF:

0.00402

Gnomad NFE exome

AF:

0.00576

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00531

AC:

7739

AN:

1456446

Hom.:

Cov.:

AF XY:

0.00511

AC XY:

3702

AN XY:

724838

show subpopulations

Gnomad4 AFR exome

AF:

0.000689

Gnomad4 AMR exome

AF:

0.00177

Gnomad4 ASJ exome

AF:

0.00656

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00169

Gnomad4 FIN exome

AF:

0.00386

Gnomad4 NFE exome

AF:

0.00622

Gnomad4 OTH exome

AF:

0.00352

GnomAD4 genome

AF:

0.00323

AC:

492

AN:

152278

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

238

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00606

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00264

Gnomad4 NFE

AF:

0.00529

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00535

Hom.:

Bravo

AF:

0.00305

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00368

AC:

447

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00371

EpiControl

AF:

0.00456

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 09, 2014	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FBN2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -

Congenital contractural arachnodactyly

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Connective tissue disorder

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Feb 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.68

D;.;D;D;D

Eigen

Benign

0.054

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;.;.;D;D

M_CAP

Benign

0.061

MetaRNN

Benign

0.013

T;T;T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

-1.5

N;.;N;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.3

D;.;D;D;D

REVEL

Uncertain

0.55

Sift

Benign

0.29

T;.;T;T;T

Sift4G

Benign

1.0

.;.;.;T;T

Polyphen

0.82

P;.;P;.;P

Vest4

0.43

MVP

0.45

MPC

0.89

ClinPred

0.036

GERP RS

4.9

Varity_R

0.29

gMVP

0.65

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