rs28763926

Positions:

• chr5-128278799-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 ENST00000262464.9(FBN2):​c.7181T>C​(p.Ile2394Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,613,968 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2394V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (17 hom.)
• Consequence: FBN2 ENST00000262464.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 7.50

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 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=0.019796938).
• BP6: Variant 5-128278799-A-G is Benign according to our data. Variant chr5-128278799-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 210999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128278799-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00269 (410/152266) while in subpopulation NFE AF= 0.00509 (346/68026). AF 95% confidence interval is 0.00464. There are 0 homozygotes in gnomad4. There are 167 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 410 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.7181T>C	p.Ile2394Thr	missense_variant	57/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.7028T>C	p.Ile2343Thr	missense_variant	56/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.7181T>C	p.Ile2394Thr	missense_variant	57/65	1	NM_001999.4	ENSP00000262464	P1
FBN2	ENST00000703783.1	n.3965T>C		non_coding_transcript_exon_variant	32/38

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 410 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00232 AC: 581 AN: 250900 Hom.: 1 AF XY: 0.00232 AC XY: 314 AN XY: 135598

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000879

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00416 AC: 6081 AN: 1461702 Hom.: 17 Cov.: 34 AF XY: 0.00415 AC XY: 3020 AN XY: 727130

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00520

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00269 AC: 410 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.00224 AC XY: 167 AN XY: 74466

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00509

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00335 Hom.: 1

Bravo AF: 0.00250

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00231 AC: 280

EpiCase AF: 0.00398

EpiControl AF: 0.00403

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:9

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2021	This variant is associated with the following publications: (PMID: 29307552, 29307550) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 06, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FBN2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -

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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Connective tissue disorder Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 31, 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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 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

Jan 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.020
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T;.;.
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-1.2	N;.;N
MutationTaster	Benign	0.94	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.98	N;.;N
REVEL	Uncertain	0.33
Sift	Benign	0.16	T;.;T
Polyphen		0.0040	B;.;B
Vest4		0.19
MVP		0.24
MPC		0.30
ClinPred		0.020	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs28763926; hg19: chr5-127614491;