rs139686090

Variant names:

• chr5-128364601-A-T
• rs139686090
• NM_001999.4:c.2427T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The ENST00000262464.9(FBN2):​c.2427T>A​(p.Ile809Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,242 control chromosomes in the GnomAD database, including 7 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00077 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: FBN2 ENST00000262464.9 splice_region, synonymous
• Scores: Splicing: ADA: 0.00005555
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -0.331
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-128364601-A-T is Benign according to our data. Variant chr5-128364601-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137319.
• BP7: Synonymous conserved (PhyloP=-0.331 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000768 (117/152338) while in subpopulation NFE AF = 0.00141 (96/68028). AF 95% confidence interval is 0.00118. There are 1 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 117 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262464.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.2427T>A	p.Ile809Ile	splice_region synonymous	Exon 18 of 65	NP_001990.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.2427T>A	p.Ile809Ile	splice_region synonymous	Exon 18 of 65	ENSP00000262464.4
	FBN2	ENST00000508989.5	TSL:2	c.2328T>A	p.Ile776Ile	splice_region synonymous	Exon 17 of 33	ENSP00000425596.1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152220 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000693 AC: 174 AN: 250998 AF XY: 0.000708

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00134 AC: 1960 AN: 1460904 Hom.: 6 Cov.: 29 AF XY: 0.00132 AC XY: 960 AN XY: 726816

African (AFR) AF: 0.000179 AC: 6 AN: 33450

American (AMR) AF: 0.000403 AC: 18 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86226

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53406

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00164 AC: 1824 AN: 1111272

Other (OTH) AF: 0.00166 AC: 100 AN: 60356

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152338 Hom.: 1 Cov.: 33 AF XY: 0.000832 AC XY: 62 AN XY: 74492

African (AFR) AF: 0.000337 AC: 14 AN: 41580

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00141 AC: 96 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.000756

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00174

EpiControl AF: 0.00196

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Congenital contractural arachnodactyly (4)
-	1	3	not provided (4)
-	-	3	not specified (3)
-	-	1	Connective tissue disorder (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.6
DANN	Benign	0.82
PhyloP100		-0.33
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000056
dbscSNV1_RF	Benign	0.10
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: rs139686090; hg19: chr5-127700294;