rs28763927

Variant names:

• chr5-128280322-A-G
• rs28763927
• NM_001999.4:c.7013-5T>C

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.7013-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 1,604,704 control chromosomes in the GnomAD database, including 4,846 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (450 hom., cov: 33)
  • Exomes 𝑓: 0.075 (4396 hom.)
• Consequence: FBN2 NM_001999.4 splice_region, intron
• Scores: Splicing: ADA: 0.0007284
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.272
• 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=-0.72).
• BP6: Variant 5-128280322-A-G is Benign according to our data. Variant chr5-128280322-A-G is described in ClinVar as Benign. ClinVar VariationId is 129048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.7013-5T>C		splice_region_variant, intron_variant	Intron 55 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6860-5T>C		splice_region_variant, intron_variant	Intron 54 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.7013-5T>C		splice_region_variant, intron_variant	Intron 55 of 64	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3797-5T>C		splice_region_variant, intron_variant	Intron 30 of 37

Frequencies

GnomAD3 genomes AF: 0.0709 AC: 10789 AN: 152122 Hom.: 450 Cov.: 33

Gnomad AFR AF: 0.0776

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0660

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.0631

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0344

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0724

Gnomad OTH AF: 0.0708

GnomAD2 exomes AF: 0.0749 AC: 18758 AN: 250328 AF XY: 0.0757

Gnomad AFR exome AF: 0.0808

Gnomad AMR exome AF: 0.0808

Gnomad ASJ exome AF: 0.0702

Gnomad EAS exome AF: 0.0606

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0744

Gnomad OTH exome AF: 0.0716

GnomAD4 exome AF: 0.0752 AC: 109262 AN: 1452464 Hom.: 4396 Cov.: 28 AF XY: 0.0760 AC XY: 54954 AN XY: 723088

African (AFR) AF: 0.0754 AC: 2511 AN: 33284

American (AMR) AF: 0.0778 AC: 3477 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0673 AC: 1754 AN: 26080

East Asian (EAS) AF: 0.0615 AC: 2433 AN: 39530

South Asian (SAS) AF: 0.0992 AC: 8536 AN: 86062

European-Finnish (FIN) AF: 0.0435 AC: 2297 AN: 52830

Middle Eastern (MID) AF: 0.120 AC: 686 AN: 5740

European-Non Finnish (NFE) AF: 0.0750 AC: 82813 AN: 1104192

Other (OTH) AF: 0.0792 AC: 4755 AN: 60056

GnomAD4 genome AF: 0.0708 AC: 10786 AN: 152240 Hom.: 450 Cov.: 33 AF XY: 0.0690 AC XY: 5137 AN XY: 74446

African (AFR) AF: 0.0776 AC: 3222 AN: 41540

American (AMR) AF: 0.0660 AC: 1009 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3470

East Asian (EAS) AF: 0.0625 AC: 324 AN: 5186

South Asian (SAS) AF: 0.102 AC: 490 AN: 4826

European-Finnish (FIN) AF: 0.0344 AC: 365 AN: 10602

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0724 AC: 4921 AN: 68000

Other (OTH) AF: 0.0705 AC: 149 AN: 2112

Alfa AF: 0.0597 Hom.: 158

Bravo AF: 0.0730

Asia WGS AF: 0.0710 AC: 249 AN: 3476

EpiCase AF: 0.0740

EpiControl AF: 0.0760

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 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. -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

7013-5T>C in intron 55 of FBN2: This variant is not expected to have clinical si gnificance because it has been identified in 8.3% (365/4404) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs28763927). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.7013-5T>C 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. ESE finder predicts the loss of an SRp40 binding motif. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been observed in a large, broad control population, ExAC, in 9206/120128 control chromosomes (389 homozygotes) at a frequency of 0.0766349, which is approximately 61308 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 classified this variant as benign. Taken together, this variant is classified as benign. -

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

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Nov 19, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.4
DANN	Benign	0.76
PhyloP100		0.27
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00073
dbscSNV1_RF	Benign	0.050
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: rs28763927; hg19: chr5-127616014; COSMIC: COSV52516898;