NM_001999.4:c.6511+5G>A

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001999.4. 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.6511+5G>A		splice_region intron	N/A	NP_001990.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.6511+5G>A		splice_region intron	N/A	ENSP00000262464.4
	FBN2	ENST00000939405.1		c.6412+5G>A		splice_region intron	N/A	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.6358+5G>A		splice_region intron	N/A	ENSP00000609463.1

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Congenital contractural arachnodactyly (2)
-	1	-	Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset (1)
-	-	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	-0.74
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;