rs117524265

chr5-128464822-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):c.728T>C(p.Ile243Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00796 in 1,614,250 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (89 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 7.46

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.01372388).
• BP6: Variant 5-128464822-A-G is Benign according to our data. Variant chr5-128464822-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 137358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128464822-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00732 (1116/152358) while in subpopulation EAS AF= 0.0489 (253/5176). AF 95% confidence interval is 0.0439. There are 11 homozygotes in gnomad4. There are 588 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1121 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.728T>C	p.Ile243Thr	missense_variant	6/65	ENST00000262464.9
FBN2	XM_017009228.3	c.728T>C	p.Ile243Thr	missense_variant	6/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.728T>C	p.Ile243Thr	missense_variant	6/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1121 AN: 152240 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0492

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00679

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00973 AC: 2446 AN: 251408 Hom.: 45 AF XY: 0.00962 AC XY: 1307 AN XY: 135868

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.0453

Gnomad SAS exome AF: 0.00392

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.00710

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00803 AC: 11732 AN: 1461892 Hom.: 89 Cov.: 32 AF XY: 0.00786 AC XY: 5719 AN XY: 727248

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00539

Gnomad4 EAS exome AF: 0.0336

Gnomad4 SAS exome AF: 0.00417

Gnomad4 FIN exome AF: 0.0218

Gnomad4 NFE exome AF: 0.00714

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00732 AC: 1116 AN: 152358 Hom.: 11 Cov.: 32 AF XY: 0.00789 AC XY: 588 AN XY: 74506

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.0489

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.0197

Gnomad4 NFE AF: 0.00679

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00795 Hom.: 12

Bravo AF: 0.00655

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00947 AC: 1150

Asia WGS AF: 0.0300 AC: 105 AN: 3478

EpiCase AF: 0.00643

EpiControl AF: 0.00593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	This variant is associated with the following publications: (PMID: 16835936, 31426022) -
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	Apr 01, 2024	FBN2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 10, 2017	- -
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.728T>C (p.Ile243Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within a TB domain (InterPro) and 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.009478 (1150/121334 control chromosomes [18 homozygotes]), which is approximately 7582 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In a study of 49 Marfan syndrome or suspected Marfan syndrome patients where several disease-related genes were sequenced, including FBN2, the variant was detected and described as a polymorphism (Sakai_FBN1_AJMGA_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2015	- -

Congenital contractural arachnodactyly Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Connective tissue disorder Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Aug 04, 2021	- -
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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2015

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

Nov 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;D;D;.
Eigen	Benign	0.054
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.45	T;.;.;T;T
MetaRNN	Benign	0.014	T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.3	L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.0	D;.;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.029	D;.;D;D;T
Polyphen		0.64	P;.;P;P;P
Vest4		0.51
MVP		0.62
MPC		0.82
ClinPred		0.039	T
GERP RS		3.6
Varity_R		0.14
gMVP		0.32

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

Other links and lift over

dbSNP: rs117524265; hg19: chr5-127800515; COSMIC: COSV52517000;