rs2291628

Variant names:

• chr5-128273941-G-A
• rs2291628
• NM_001999.4:c.7739C>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.7739C>T​(p.Ser2580Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0746 in 1,613,668 control chromosomes in the GnomAD database, including 4,830 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2580S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.071 (436 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4394 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.193
• Publications: 23 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 (MetaRNN=0.0017172396).
• BP6: Variant 5-128273941-G-A is Benign according to our data. Variant chr5-128273941-G-A is described in ClinVar as Benign. ClinVar VariationId is 129051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0813 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.7739C>T	p.Ser2580Leu	missense	Exon 61 of 65	NP_001990.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.7739C>T	p.Ser2580Leu	missense	Exon 61 of 65	ENSP00000262464.4
	FBN2	ENST00000939405.1		c.7640C>T	p.Ser2547Leu	missense	Exon 60 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.7586C>T	p.Ser2529Leu	missense	Exon 60 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.0707 AC: 10753 AN: 152072 Hom.: 436 Cov.: 32

Gnomad AFR AF: 0.0754

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0693

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0635

Gnomad SAS AF: 0.0891

Gnomad FIN AF: 0.0347

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0718

Gnomad OTH AF: 0.0681

GnomAD2 exomes AF: 0.0741 AC: 18579 AN: 250880 AF XY: 0.0736

Gnomad AFR exome AF: 0.0792

Gnomad AMR exome AF: 0.0839

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0603

Gnomad FIN exome AF: 0.0440

Gnomad NFE exome AF: 0.0735

Gnomad OTH exome AF: 0.0735

GnomAD4 exome AF: 0.0750 AC: 109644 AN: 1461478 Hom.: 4394 Cov.: 32 AF XY: 0.0753 AC XY: 54738 AN XY: 727060

African (AFR) AF: 0.0753 AC: 2519 AN: 33468

American (AMR) AF: 0.0808 AC: 3612 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2758 AN: 26124

East Asian (EAS) AF: 0.0616 AC: 2444 AN: 39674

South Asian (SAS) AF: 0.0811 AC: 6997 AN: 86238

European-Finnish (FIN) AF: 0.0435 AC: 2321 AN: 53406

Middle Eastern (MID) AF: 0.110 AC: 637 AN: 5768

European-Non Finnish (NFE) AF: 0.0751 AC: 83450 AN: 1111716

Other (OTH) AF: 0.0813 AC: 4906 AN: 60376

GnomAD4 genome AF: 0.0706 AC: 10751 AN: 152190 Hom.: 436 Cov.: 32 AF XY: 0.0683 AC XY: 5083 AN XY: 74402

African (AFR) AF: 0.0754 AC: 3130 AN: 41530

American (AMR) AF: 0.0693 AC: 1059 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3472

East Asian (EAS) AF: 0.0629 AC: 325 AN: 5168

South Asian (SAS) AF: 0.0882 AC: 425 AN: 4820

European-Finnish (FIN) AF: 0.0347 AC: 368 AN: 10610

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0718 AC: 4883 AN: 67994

Other (OTH) AF: 0.0678 AC: 143 AN: 2108

Alfa AF: 0.0732 Hom.: 1740

Bravo AF: 0.0733

TwinsUK AF: 0.0761 AC: 282

ALSPAC AF: 0.0791 AC: 305

ESP6500AA AF: 0.0813 AC: 358

ESP6500EA AF: 0.0764 AC: 657

ExAC AF: 0.0743 AC: 9017

Asia WGS AF: 0.0660 AC: 230 AN: 3478

EpiCase AF: 0.0733

EpiControl AF: 0.0751

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Congenital contractural arachnodactyly (4)
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.19
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.23
Sift	Uncertain	0.029	D
Polyphen		0.0010	B
Vest4		0.19
MPC		0.22
ClinPred		0.021	T
GERP RS		3.9
Varity_R		0.14
gMVP		0.65
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2291628; hg19: chr5-127609633; COSMIC: COSV52516875;