rs56168072

Positions:

• chr5-128330606-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):​c.4312G>A​(p.Glu1438Lys) variant causes a missense change. The variant allele was found at a frequency of 0.01 in 1,614,008 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (5 hom., cov: 33)
  • Exomes 𝑓: 0.010 (123 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 5.96

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• PM1: In a hotspot region, there are 3 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 where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.018452108).
• BP6: Variant 5-128330606-C-T is Benign according to our data. Variant chr5-128330606-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128330606-C-T is described in Lovd as [Likely_benign]. Variant chr5-128330606-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00814 (1239/152268) while in subpopulation NFE AF= 0.012 (817/68020). AF 95% confidence interval is 0.0113. There are 5 homozygotes in gnomad4. There are 616 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1239 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.4312G>A	p.Glu1438Lys	missense_variant	33/65	ENST00000262464.9
FBN2	XM_017009228.3	c.4159G>A	p.Glu1387Lys	missense_variant	32/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.4312G>A	p.Glu1438Lys	missense_variant	33/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 1239 AN: 152150 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00958

GnomAD3 exomes AF: 0.00801 AC: 2013 AN: 251322 Hom.: 17 AF XY: 0.00833 AC XY: 1131 AN XY: 135838

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00218

Gnomad SAS exome AF: 0.00578

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00913

GnomAD4 exome AF: 0.0102 AC: 14954 AN: 1461740 Hom.: 123 Cov.: 31 AF XY: 0.0104 AC XY: 7532 AN XY: 727184

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00472

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.00118

Gnomad4 SAS exome AF: 0.00614

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.00969

GnomAD4 genome AF: 0.00814 AC: 1239 AN: 152268 Hom.: 5 Cov.: 33 AF XY: 0.00827 AC XY: 616 AN XY: 74444

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.0105 Hom.: 16

Bravo AF: 0.00751

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0112 AC: 96

ExAC AF: 0.00795 AC: 965

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0130

EpiControl AF: 0.0121

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 23, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Glu1438Lys in exon 33 of FBN2: This variant is not expected to have clinical sig nificance because it has been identified in 1.1% (96/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs56168072). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2013	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. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
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 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2017	Variant summary: The FBN2 c.4312G>A (p.Glu1438Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 964/121286 control chromosomes (10 homozygotes) at a frequency of 0.0079482, which is approximately 170 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000469), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Congenital contractural arachnodactyly Benign:4

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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2014

This alteration is classified as 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

May 27, 2022

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;D;D;D
Eigen	Benign	-0.020
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;.;D;D
MetaRNN	Benign	0.018	T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.3	L;.;L;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N;.;N;D;N
REVEL	Uncertain	0.48
Sift	Benign	0.076	T;.;T;T;T
Polyphen		0.34	B;.;B;.;P
Vest4		0.74
MVP		0.45
MPC		0.43
ClinPred		0.017	T
GERP RS		4.2
Varity_R		0.17
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs56168072; hg19: chr5-127666298; COSMIC: COSV52532764;