rs28763927

Positions:

• chr5-128280322-A-G

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.7013-5T>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0007284
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.272

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=-0.72).
• BP6: Variant 5-128280322-A-G is Benign according to our data. Variant chr5-128280322-A-G is described in ClinVar as [Benign]. Clinvar id is 129048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128280322-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
FBN2	NM_001999.4	c.7013-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262464.9
FBN2	XM_017009228.3	c.6860-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.7013-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.3797-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.0749 AC: 18758 AN: 250328 Hom.: 761 AF XY: 0.0757 AC XY: 10237 AN XY: 135304

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 SAS exome AF: 0.0993

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

Gnomad4 AFR exome AF: 0.0754

Gnomad4 AMR exome AF: 0.0778

Gnomad4 ASJ exome AF: 0.0673

Gnomad4 EAS exome AF: 0.0615

Gnomad4 SAS exome AF: 0.0992

Gnomad4 FIN exome AF: 0.0435

Gnomad4 NFE exome AF: 0.0750

Gnomad4 OTH exome AF: 0.0792

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

Gnomad4 AFR AF: 0.0776

Gnomad4 AMR AF: 0.0660

Gnomad4 ASJ AF: 0.0689

Gnomad4 EAS AF: 0.0625

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.0344

Gnomad4 NFE AF: 0.0724

Gnomad4 OTH AF: 0.0705

Alfa AF: 0.0592 Hom.: 148

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

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	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). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2017	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

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2014

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs28763927; hg19: chr5-127616014; COSMIC: COSV52516898;