rs586115

Variant names:

• chr5-128327183-T-C
• rs586115
• NM_001999.4:c.4471+1513A>G

Variant summary

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

The NM_001999.4(FBN2):​c.4471+1513A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,188 control chromosomes in the GnomAD database, including 3,532 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 0.21 (3532 hom., cov: 32)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.318
• Publications: 2 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 (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.4471+1513A>G		intron_variant	Intron 34 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.4318+1513A>G		intron_variant	Intron 33 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.4471+1513A>G		intron_variant	Intron 34 of 64	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.1255+1513A>G		intron_variant	Intron 9 of 37
FBN2	ENST00000703785.1	n.1336+1513A>G		intron_variant	Intron 9 of 26

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32283 AN: 152070 Hom.: 3528 Cov.: 32

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.223

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

GnomAD4 genome AF: 0.212 AC: 32301 AN: 152188 Hom.: 3532 Cov.: 32 AF XY: 0.206 AC XY: 15353 AN XY: 74408

African (AFR) AF: 0.247 AC: 10235 AN: 41500

American (AMR) AF: 0.217 AC: 3313 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 853 AN: 3466

East Asian (EAS) AF: 0.119 AC: 618 AN: 5184

South Asian (SAS) AF: 0.198 AC: 957 AN: 4822

European-Finnish (FIN) AF: 0.117 AC: 1242 AN: 10610

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14365 AN: 68002

Other (OTH) AF: 0.220 AC: 466 AN: 2114

Alfa AF: 0.211 Hom.: 445

Bravo AF: 0.225

Asia WGS AF: 0.152 AC: 534 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.8
DANN	Benign	0.32
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs586115; hg19: chr5-127662875;