rs27713

Positions:

• chr5-128305091-G-A
• chr5-128305091-G-C
• chr5-128305091-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001999.4(FBN2):​c.5675-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,572,472 control chromosomes in the GnomAD database, including 381,980 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (34471 hom., cov: 31)
  • Exomes 𝑓: 0.70 (347509 hom.)
• Consequence: FBN2 NM_001999.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001468
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.918

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-128305091-G-A is Benign according to our data. Variant chr5-128305091-G-A is described in ClinVar as [Benign]. Clinvar id is 129043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128305091-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.5675-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262464.9
FBN2	XM_017009228.3	c.5522-9C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.5675-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.2459-9C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
FBN2	ENST00000703785.1	n.2378-9C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.693 AC: 101358 AN: 146238 Hom.: 34438 Cov.: 31

Gnomad AFR AF: 0.616

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.703

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.849

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.758

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.671

GnomAD3 exomes AF: 0.708 AC: 166381 AN: 235054 Hom.: 59360 AF XY: 0.713 AC XY: 90372 AN XY: 126790

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.675

Gnomad ASJ exome AF: 0.708

Gnomad EAS exome AF: 0.858

Gnomad SAS exome AF: 0.740

Gnomad FIN exome AF: 0.767

Gnomad NFE exome AF: 0.698

Gnomad OTH exome AF: 0.713

GnomAD4 exome AF: 0.698 AC: 995491 AN: 1426126 Hom.: 347509 Cov.: 29 AF XY: 0.701 AC XY: 497590 AN XY: 710328

Gnomad4 AFR exome AF: 0.611

Gnomad4 AMR exome AF: 0.683

Gnomad4 ASJ exome AF: 0.715

Gnomad4 EAS exome AF: 0.859

Gnomad4 SAS exome AF: 0.744

Gnomad4 FIN exome AF: 0.771

Gnomad4 NFE exome AF: 0.688

Gnomad4 OTH exome AF: 0.690

GnomAD4 genome AF: 0.693 AC: 101440 AN: 146346 Hom.: 34471 Cov.: 31 AF XY: 0.697 AC XY: 49903 AN XY: 71548

Gnomad4 AFR AF: 0.617

Gnomad4 AMR AF: 0.703

Gnomad4 ASJ AF: 0.705

Gnomad4 EAS AF: 0.849

Gnomad4 SAS AF: 0.755

Gnomad4 FIN AF: 0.769

Gnomad4 NFE AF: 0.704

Gnomad4 OTH AF: 0.674

Alfa AF: 0.560 Hom.: 9722

Bravo AF: 0.651

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	5675-9C>T in intron 44 of FBN2: This variant is not expected to have clinical si gnificance because it has been identified in 86.5% (173/200) of Han Chinese chro mosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm .nih.gov/projects/SNP; dbSNP rs60746914). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2012	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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital contractural arachnodactyly Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2016

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. -

Macular degeneration, early-onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.41
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.034
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: rs27713; hg19: chr5-127640783;