chr5-128289877-C-T

Variant names:

• chr5-128289877-C-T
• rs200608284
• NM_001999.4:c.6511+5G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001999.4(FBN2):​c.6511+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,540,266 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (29 hom.)
• Consequence: FBN2 NM_001999.4 splice_region, intron
• Scores: Splicing: ADA: 0.9725
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.630
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-128289877-C-T is Benign according to our data. Variant chr5-128289877-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137344.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00345 (525/152150) while in subpopulation NFE AF = 0.00638 (434/68006). AF 95% confidence interval is 0.00589. There are 5 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 525 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6511+5G>A		splice_region_variant, intron_variant	Intron 51 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6358+5G>A		splice_region_variant, intron_variant	Intron 50 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6511+5G>A		splice_region_variant, intron_variant	Intron 51 of 64	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3295+5G>A		splice_region_variant, intron_variant	Intron 26 of 37
FBN2	ENST00000703785.1	n.3214+5G>A		splice_region_variant, intron_variant	Intron 25 of 26

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 525 AN: 152032 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00390 AC: 973 AN: 249676 AF XY: 0.00401

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00278

Gnomad NFE exome AF: 0.00742

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00458 AC: 6352 AN: 1388116 Hom.: 29 Cov.: 24 AF XY: 0.00449 AC XY: 3119 AN XY: 695020

African (AFR) AF: 0.000842 AC: 27 AN: 32084

American (AMR) AF: 0.000651 AC: 29 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.000701 AC: 18 AN: 25676

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39242

South Asian (SAS) AF: 0.0000947 AC: 8 AN: 84462

European-Finnish (FIN) AF: 0.00310 AC: 165 AN: 53288

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5608

European-Non Finnish (NFE) AF: 0.00567 AC: 5931 AN: 1045390

Other (OTH) AF: 0.00298 AC: 172 AN: 57788

GnomAD4 genome AF: 0.00345 AC: 525 AN: 152150 Hom.: 5 Cov.: 32 AF XY: 0.00323 AC XY: 240 AN XY: 74390

African (AFR) AF: 0.000819 AC: 34 AN: 41524

American (AMR) AF: 0.00138 AC: 21 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00638 AC: 434 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00508 Hom.: 4

Bravo AF: 0.00312

EpiCase AF: 0.00465

EpiControl AF: 0.00493

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Mar 22, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The FBN2 c.6511+5G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and ESE Finder predicts no significant effect on ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in ExAC at a frequency of 0.0049729 (549/110398 control chromosomes [2 homozygotes]), which is approximately 3978 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Oct 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FBN2: BP4, BS1, BS2 -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2014

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. -

Congenital contractural arachnodactyly Benign:2

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset Uncertain:1

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FBN2 NM_001999 exon 51 c.6511+5G>A: This variant has not been reported in the literature but is present in 0.7% (894/125710) of European individuals including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs200608284). This variant is present in ClinVar, with several labs classifying this variant as likely benign or benign (Variation ID:137344). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Jun 04, 2015

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. -

Ehlers-Danlos syndrome Benign:1

Jun 03, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Connective tissue disorder Benign:1

Feb 18, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

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	-0.74
CADD	Benign	17
DANN	Benign	0.44
PhyloP100		0.63
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.66
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: rs200608284; hg19: chr5-127625569;