rs11960575

Variant names:

• chr5-128497163-C-T
• rs11960575
• NM_001999.4:c.628+22110G>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+22110G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 152,026 control chromosomes in the GnomAD database, including 13,304 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 0.33 (13304 hom., cov: 32)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.471
• Publications: 6 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.73 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.628+22110G>A		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.628+22110G>A		intron	N/A	ENSP00000262464.4
	FBN2	ENST00000502468.5	TSL:1	c.628+22110G>A		intron	N/A	ENSP00000424753.1
	FBN2	ENST00000508989.5	TSL:2	c.529+22110G>A		intron	N/A	ENSP00000425596.1

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50295 AN: 151908 Hom.: 13253 Cov.: 32

Gnomad AFR AF: 0.736

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.285

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

GnomAD4 genome AF: 0.332 AC: 50411 AN: 152026 Hom.: 13304 Cov.: 32 AF XY: 0.327 AC XY: 24322 AN XY: 74320

African (AFR) AF: 0.737 AC: 30543 AN: 41454

American (AMR) AF: 0.218 AC: 3326 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 698 AN: 3468

East Asian (EAS) AF: 0.112 AC: 581 AN: 5168

South Asian (SAS) AF: 0.282 AC: 1359 AN: 4820

European-Finnish (FIN) AF: 0.169 AC: 1780 AN: 10556

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11310 AN: 67966

Other (OTH) AF: 0.285 AC: 601 AN: 2110

Alfa AF: 0.217 Hom.: 20099

Bravo AF: 0.350

Asia WGS AF: 0.260 AC: 903 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.61
DANN	Benign	0.22
PhyloP100		-0.47
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: rs11960575; hg19: chr5-127832856; COSMIC: COSV52502347;