rs200608284

chr5-128289877-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001999.4(FBN2):c.6511+5G>A variant causes a splice donor 5th base, 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_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9725
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.630

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 -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 id is 137344.We mark this variant Likely_benign, oryginal submissions are: {Benign=10, Uncertain_significance=1, Likely_benign=1}. Variant chr5-128289877-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 525 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.6511+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000262464.9
FBN2	XM_017009228.3	c.6358+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.6511+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.3295+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant
FBN2	ENST00000703785.1	n.3214+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.00390 AC: 973 AN: 249676 Hom.: 3 AF XY: 0.00401 AC XY: 541 AN XY: 134976

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 SAS exome AF: 0.000132

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

Gnomad4 AFR exome AF: 0.000842

Gnomad4 AMR exome AF: 0.000651

Gnomad4 ASJ exome AF: 0.000701

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000947

Gnomad4 FIN exome AF: 0.00310

Gnomad4 NFE exome AF: 0.00567

Gnomad4 OTH exome AF: 0.00298

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

Gnomad4 AFR AF: 0.000819

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00638

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00537 Hom.: 2

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

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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.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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FBN2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2014	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	Eurofins Ntd Llc (ga)	Sep 05, 2014	- -

Congenital contractural arachnodactyly Benign:2

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	Invitae	Jan 29, 2024	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2015

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 03, 2022

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	17
Dann	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs200608284; hg19: chr5-127625569;