chr5-128380874-C-A

Variant names:

• chr5-128380874-C-A
• rs17608902
• NM_001999.4:c.1604-1984G>T

Variant summary

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

The NM_001999.4(FBN2):​c.1604-1984G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0636 in 151,990 control chromosomes in the GnomAD database, including 403 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 0.064 (403 hom., cov: 32)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88
• Publications: 8 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0863 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.1604-1984G>T		intron	N/A	NP_001990.2	P35556-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.1604-1984G>T		intron	N/A	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.1505-1984G>T		intron	N/A	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.1451-1984G>T		intron	N/A	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 9672 AN: 151870 Hom.: 404 Cov.: 32

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.0629

Gnomad SAS AF: 0.0446

Gnomad FIN AF: 0.0920

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0882

Gnomad OTH AF: 0.0659

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

GnomAD4 genome AF: 0.0636 AC: 9665 AN: 151990 Hom.: 403 Cov.: 32 AF XY: 0.0622 AC XY: 4617 AN XY: 74278

African (AFR) AF: 0.0240 AC: 998 AN: 41498

American (AMR) AF: 0.0507 AC: 771 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.0628 AC: 325 AN: 5172

South Asian (SAS) AF: 0.0440 AC: 212 AN: 4816

European-Finnish (FIN) AF: 0.0920 AC: 971 AN: 10560

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0882 AC: 5991 AN: 67946

Other (OTH) AF: 0.0652 AC: 137 AN: 2102

Alfa AF: 0.0212 Hom.: 11

Bravo AF: 0.0604

Asia WGS AF: 0.0640 AC: 220 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.20
DANN	Benign	0.73
PhyloP100		-1.9
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: rs17608902; hg19: chr5-127716567;