rs1435514

Variant names:

• chr5-128506726-C-T
• rs1435514
• NM_001999.4:c.628+12547G>A

Variant summary

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

The NM_001999.4(FBN2):​c.628+12547G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 151,930 control chromosomes in the GnomAD database, including 22,040 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 0.50 (22040 hom., cov: 32)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0150
• 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 (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.628+12547G>A		intron_variant	Intron 5 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.628+12547G>A		intron_variant	Intron 5 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.628+12547G>A		intron_variant	Intron 5 of 64	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75431 AN: 151812 Hom.: 21987 Cov.: 32

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.450

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

GnomAD4 genome AF: 0.497 AC: 75549 AN: 151930 Hom.: 22040 Cov.: 32 AF XY: 0.488 AC XY: 36236 AN XY: 74256

African (AFR) AF: 0.820 AC: 34029 AN: 41492

American (AMR) AF: 0.351 AC: 5362 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1297 AN: 3470

East Asian (EAS) AF: 0.218 AC: 1130 AN: 5176

South Asian (SAS) AF: 0.433 AC: 2085 AN: 4816

European-Finnish (FIN) AF: 0.342 AC: 3617 AN: 10564

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.392 AC: 26593 AN: 67834

Other (OTH) AF: 0.449 AC: 948 AN: 2110

Alfa AF: 0.464 Hom.: 2435

Bravo AF: 0.509

Asia WGS AF: 0.398 AC: 1384 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.7
DANN	Benign	0.49
PhyloP100		-0.015
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: rs1435514; hg19: chr5-127842419; COSMIC: COSV52502486;