5-128527886-G-A

Variant names:

• chr5-128527886-G-A
• rs147157552
• NM_001999.4:c.518C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001999.4(FBN2):​c.518C>T​(p.Thr173Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,608,094 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 4.49
• Publications: 11 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001999.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.017662913).
• BP6: Variant 5-128527886-G-A is Benign according to our data. Variant chr5-128527886-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 155796.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00108 (165/152250) while in subpopulation NFE AF = 0.00194 (132/68008). AF 95% confidence interval is 0.00167. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 165 AD gene.

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.518C>T	p.Thr173Ile	missense	Exon 4 of 65	NP_001990.2	P35556-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.518C>T	p.Thr173Ile	missense	Exon 4 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000502468.5	TSL:1	c.518C>T	p.Thr173Ile	missense	Exon 4 of 8	ENSP00000424753.1	E9PHW4
	FBN2	ENST00000939405.1		c.419C>T	p.Thr140Ile	missense	Exon 3 of 64	ENSP00000609464.1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00116 AC: 292 AN: 250682 AF XY: 0.00125

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00130 AC: 1898 AN: 1455844 Hom.: 3 Cov.: 29 AF XY: 0.00134 AC XY: 969 AN XY: 724632

African (AFR) AF: 0.000240 AC: 8 AN: 33314

American (AMR) AF: 0.000718 AC: 32 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.000163 AC: 14 AN: 86116

European-Finnish (FIN) AF: 0.00109 AC: 58 AN: 53348

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.00153 AC: 1699 AN: 1106914

Other (OTH) AF: 0.00141 AC: 85 AN: 60146

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74448

African (AFR) AF: 0.000217 AC: 9 AN: 41556

American (AMR) AF: 0.000719 AC: 11 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00194 AC: 132 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00171 Hom.: 2

Bravo AF: 0.00104

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00135 AC: 164

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00186

EpiControl AF: 0.00154

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	2	Congenital contractural arachnodactyly (2)
-	-	2	Connective tissue disorder (2)
-	1	1	Familial thoracic aortic aneurysm and aortic dissection (2)
-	1	1	not specified (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	FBN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.5
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.32
Sift	Benign	0.045	D
Sift4G	Uncertain	0.026	D
Polyphen		0.047	B
Vest4		0.38
MVP		0.35
MPC		0.53
ClinPred		0.029	T
GERP RS		3.2
Varity_R		0.096
gMVP		0.10
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147157552; hg19: chr5-127863579;