rs27713

Variant names:

• chr5-128305091-G-A
• rs27713
• NM_001999.4:c.5675-9C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001999.4(FBN2):​c.5675-9C>T variant causes a 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 intron
• Scores: Splicing: ADA: 0.00001468
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.918
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• congenital contractural arachnodactyly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.5675-9C>T		intron_variant	Intron 44 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.5522-9C>T		intron_variant	Intron 43 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.5675-9C>T		intron_variant	Intron 44 of 64	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.2459-9C>T		intron_variant	Intron 19 of 37
FBN2	ENST00000703785.1	n.2378-9C>T		intron_variant	Intron 18 of 26

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

GnomAD2 exomes AF: 0.708 AC: 166381 AN: 235054 AF XY: 0.713

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 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

African (AFR) AF: 0.611 AC: 17606 AN: 28802

American (AMR) AF: 0.683 AC: 29219 AN: 42764

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 18470 AN: 25836

East Asian (EAS) AF: 0.859 AC: 33677 AN: 39220

South Asian (SAS) AF: 0.744 AC: 62916 AN: 84524

European-Finnish (FIN) AF: 0.771 AC: 40797 AN: 52940

Middle Eastern (MID) AF: 0.732 AC: 4159 AN: 5684

European-Non Finnish (NFE) AF: 0.688 AC: 748017 AN: 1087482

Other (OTH) AF: 0.690 AC: 40630 AN: 58874

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

African (AFR) AF: 0.617 AC: 22285 AN: 36140

American (AMR) AF: 0.703 AC: 10587 AN: 15070

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2441 AN: 3464

East Asian (EAS) AF: 0.849 AC: 4374 AN: 5154

South Asian (SAS) AF: 0.755 AC: 3634 AN: 4814

European-Finnish (FIN) AF: 0.769 AC: 8092 AN: 10516

Middle Eastern (MID) AF: 0.753 AC: 220 AN: 292

European-Non Finnish (NFE) AF: 0.704 AC: 47849 AN: 67924

Other (OTH) AF: 0.674 AC: 1388 AN: 2060

Alfa AF: 0.592 Hom.: 13290

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Congenital contractural arachnodactyly Benign:6

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Aug 15, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.41
DANN	Benign	0.74
PhyloP100		0.92
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs27713; hg19: chr5-127640783;