chr5-128261818-G-A

Position:

chr5-128261818-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001999.4(FBN2):c.8282C>T(p.Ala2761Val) variant causes a missense change. The variant allele was found at a frequency of 0.000216 in 1,614,010 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 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:4

Conservation

PhyloP100: 5.65

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.

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=0.19253772).

BP6

Variant 5-128261818-G-A is Benign according to our data. Variant chr5-128261818-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213370.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=7}. Variant chr5-128261818-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000217 (33/152228) while in subpopulation AMR AF= 0.000654 (10/15286). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.8282C>T	p.Ala2761Val	missense_variant	64/65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 linkuse as main transcript	c.8129C>T	p.Ala2710Val	missense_variant	63/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.8282C>T	p.Ala2761Val	missense_variant	64/65	1	NM_001999.4	ENSP00000262464.4		P35556-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000207

AC:

AN:

251164

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000216

AC:

316

AN:

1461782

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

144

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000247

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000217

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.000253

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital contractural arachnodactyly

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS–3C. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine (exon 64). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (55 heterozygotes, 0 homozygotes). (P) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant previously been described as variant of uncertain significance (VUS). Six VUS entries in ClinVar. Previously observed in the VCGS cardiomyopathy cohort. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) – Pathogenic, (N) – Neutral, (B) – Benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2024	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18767143) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2017	The p.Ala2761Val variant (rs201962592) has not been reported in the medical literature, gene specific variation databases, but it has been reported to ClinVar (see link below). This variant is listed in the Exome Aggregation Consortium Browser with a population frequency of 0.03 percent (identified on 20 out of 66,740 chromosomes) in non-Finnish European population. The alanine at position 2761 is highly conserved (up to Chicken, considering 11 species) (Alamut v.2.8.1) but Zebra-finch has valine at this position, and this non-cysteine residue is not located in the EGF-like domain. Computational analyses of the effects of the p.Ala2761Val variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Our laboratory has previously identified this variant in one individual with bifid uvula, submucous cleft, micrognathia, facial asymmetry, joint hypermobility, tracheomalacia, conductive hearing loss and developmental delay. Altogether, there is not enough evidence to classify the p.Ala2761Val variant with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FBN2: BP4 -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2023

The p.A2761V variant (also known as c.8282C>T), located in coding exon 64 of the FBN2 gene, results from a C to T substitution at nucleotide position 8282. The alanine at codon 2761 is replaced by valine, an amino acid with similar properties, and is located in the fibulin-like domain. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

May 27, 2019

ACMG classification criteria: PM2, BP4 -

Connective tissue disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2019

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 22, 2024

Variant summary: FBN2 c.8282C>T (p.Ala2761Val) 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 0.00021 in 251164 control chromosomes (gnomAD v2.1). The observed variant frequency is approximately 165-fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN2 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.8282C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 213370). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.;D

Eigen

Benign

0.097

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;.;.

M_CAP

Benign

0.023

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.5

M;.;M

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.6

D;.;D

REVEL

Uncertain

0.33

Sift

Benign

0.11

T;.;T

Polyphen

0.0010

B;.;B

Vest4

0.23

MVP

0.51

MPC

0.28

ClinPred

0.094

GERP RS

5.5

Varity_R

0.076

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