chr5-128349932-C-A

Variant names:

• chr5-128349932-C-A
• rs255690
• NM_001999.4:c.2863+23G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001999.4(FBN2):​c.2863+23G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,577,716 control chromosomes in the GnomAD database, including 84,803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5731 hom., cov: 33)
  • Exomes 𝑓: 0.32 (79072 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.271
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-128349932-C-A is Benign according to our data. Variant chr5-128349932-C-A is described in ClinVar as Benign. ClinVar VariationId is 258514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.343 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.2863+23G>T		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.2863+23G>T		intron	N/A	ENSP00000262464.4
	FBN2	ENST00000508989.5	TSL:2	c.2764+23G>T		intron	N/A	ENSP00000425596.1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38085 AN: 152080 Hom.: 5728 Cov.: 33

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.271

GnomAD2 exomes AF: 0.280 AC: 70163 AN: 250474 AF XY: 0.281

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.332

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.289

GnomAD4 exome AF: 0.324 AC: 462250 AN: 1425518 Hom.: 79072 Cov.: 27 AF XY: 0.322 AC XY: 229060 AN XY: 711380

African (AFR) AF: 0.0968 AC: 3200 AN: 33048

American (AMR) AF: 0.326 AC: 14557 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 7277 AN: 25930

East Asian (EAS) AF: 0.114 AC: 4505 AN: 39546

South Asian (SAS) AF: 0.238 AC: 20374 AN: 85582

European-Finnish (FIN) AF: 0.202 AC: 10780 AN: 53370

Middle Eastern (MID) AF: 0.288 AC: 1642 AN: 5708

European-Non Finnish (NFE) AF: 0.354 AC: 381877 AN: 1078516

Other (OTH) AF: 0.305 AC: 18038 AN: 59188

GnomAD4 genome AF: 0.250 AC: 38092 AN: 152198 Hom.: 5731 Cov.: 33 AF XY: 0.240 AC XY: 17891 AN XY: 74406

African (AFR) AF: 0.107 AC: 4455 AN: 41530

American (AMR) AF: 0.293 AC: 4481 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 988 AN: 3468

East Asian (EAS) AF: 0.118 AC: 611 AN: 5176

South Asian (SAS) AF: 0.230 AC: 1112 AN: 4830

European-Finnish (FIN) AF: 0.183 AC: 1937 AN: 10600

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23568 AN: 67984

Other (OTH) AF: 0.268 AC: 567 AN: 2114

Alfa AF: 0.314 Hom.: 10608

Bravo AF: 0.254

Asia WGS AF: 0.158 AC: 552 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.1
DANN	Benign	0.66
PhyloP100		-0.27
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: rs255690; hg19: chr5-127685624;