rs199665922

chr5-128328713-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PP2 PP3 BP4_Strong BP6 BS1 BS2

The NM_001999.4(FBN2):c.4454A>G(p.Asp1485Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1485N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 8.01

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBN2
• PP3: Multiple lines of computational evidence support a deleterious effect 6: BayesDel_addAF, BayesDel_noAF, Cadd, phyloP100way_vertebrate, PROVEAN, REVEL [when AlphaMissense, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.032268822).
• BP6: Variant 5-128328713-T-C is Benign according to our data. Variant chr5-128328713-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213328.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=4}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00027 (394/1461832) while in subpopulation SAS AF= 0.000325 (28/86246). AF 95% confidence interval is 0.00023. There are 1 homozygotes in gnomad4_exome. There are 216 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.4454A>G	p.Asp1485Gly	missense_variant	34/65	ENST00000262464.9
FBN2	XM_017009228.3	c.4301A>G	p.Asp1434Gly	missense_variant	33/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.4454A>G	p.Asp1485Gly	missense_variant	34/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000450 AC: 113 AN: 251264 Hom.: 0 AF XY: 0.000501 AC XY: 68 AN XY: 135798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000270 AC: 394 AN: 1461832 Hom.: 1 Cov.: 31 AF XY: 0.000297 AC XY: 216 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000492 Hom.: 0

Bravo AF: 0.000332

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2020	This variant is associated with the following publications: (PMID: 25944730, 28087566) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 30, 2020	- -

Congenital contractural arachnodactyly Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	- -

Connective tissue disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 04, 2023

Variant summary: FBN2 c.4454A>G (p.Asp1485Gly) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 1614050 control chromosomes, predominantly at a frequency of 0.01 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 8000 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN2 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. To our knowledge, no occurrence of c.4454A>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1), likely benign (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;D;D;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.;.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.032	T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.4	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.0	D;.;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0090	D;.;D;D;D
Polyphen		1.0	D;.;D;.;P
Vest4		0.86
MVP		0.89
MPC		0.90
ClinPred		0.14	T
GERP RS		5.0
Varity_R		0.62
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199665922; hg19: chr5-127664405;