NM_001999.4:c.3599-507G>C

Variant names:

• chr5-128336620-C-G
• rs32222
• NM_001999.4:c.3599-507G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001999.4(FBN2):​c.3599-507G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 151,998 control chromosomes in the GnomAD database, including 18,474 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (18474 hom., cov: 32)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.406
• Publications: 3 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.3599-507G>C		intron_variant	Intron 27 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.3446-507G>C		intron_variant	Intron 26 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.3599-507G>C		intron_variant	Intron 27 of 64	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73533 AN: 151880 Hom.: 18463 Cov.: 32

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.480

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.484 AC: 73580 AN: 151998 Hom.: 18474 Cov.: 32 AF XY: 0.494 AC XY: 36708 AN XY: 74276

African (AFR) AF: 0.372 AC: 15419 AN: 41462

American (AMR) AF: 0.541 AC: 8270 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1831 AN: 3470

East Asian (EAS) AF: 0.805 AC: 4160 AN: 5170

South Asian (SAS) AF: 0.548 AC: 2626 AN: 4794

European-Finnish (FIN) AF: 0.613 AC: 6468 AN: 10548

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.489 AC: 33207 AN: 67966

Other (OTH) AF: 0.486 AC: 1023 AN: 2106

Alfa AF: 0.390 Hom.: 1365

Bravo AF: 0.470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.2
DANN	Benign	0.40
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs32222; hg19: chr5-127672312;