rs28763926

Variant names:

• chr5-128278799-A-G
• rs28763926
• NM_001999.4:c.7181T>C
• FBN2 p.Ile2394Thr

Your query was ambiguous. Multiple possible variants found:

• chr5-128278799-A-G
• chr5-128278799-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):​c.7181T>C​(p.Ile2394Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,613,968 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2394V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (17 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 7.50
• Publications: 9 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, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019796938).
• BP6: Variant 5-128278799-A-G is Benign according to our data. Variant chr5-128278799-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00269 (410/152266) while in subpopulation NFE AF = 0.00509 (346/68026). AF 95% confidence interval is 0.00464. There are 0 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 410 AD,Unknown 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.7181T>C	p.Ile2394Thr	missense	Exon 57 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.7181T>C	p.Ile2394Thr	missense	Exon 57 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.7082T>C	p.Ile2361Thr	missense	Exon 56 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.7028T>C	p.Ile2343Thr	missense	Exon 56 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 410 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00232 AC: 581 AN: 250900 AF XY: 0.00232

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000879

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00416 AC: 6081 AN: 1461702 Hom.: 17 Cov.: 34 AF XY: 0.00415 AC XY: 3020 AN XY: 727130

African (AFR) AF: 0.000597 AC: 20 AN: 33478

American (AMR) AF: 0.000559 AC: 25 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86226

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53370

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.00520 AC: 5787 AN: 1111940

Other (OTH) AF: 0.00227 AC: 137 AN: 60390

GnomAD4 genome AF: 0.00269 AC: 410 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.00224 AC XY: 167 AN XY: 74466

African (AFR) AF: 0.000698 AC: 29 AN: 41548

American (AMR) AF: 0.000720 AC: 11 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00509 AC: 346 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00336 Hom.: 2

Bravo AF: 0.00250

EpiCase AF: 0.00398

EpiControl AF: 0.00403

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not provided (10)
-	-	3	not specified (3)
-	-	2	Congenital contractural arachnodactyly (2)
-	-	2	Connective tissue disorder (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.020
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-1.2	N
PhyloP100		7.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.33
Sift	Benign	0.16	T
Varity_R		0.11
gMVP		0.60
Mutation Taster		=83/17	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs28763926;

hg19: chr5-127614491;