rs149071226

chr5-128289213-T-Achr5-128289213-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PP2 PP3 BP4_Moderate BP6 BS1 BS2

The NM_001999.4(FBN2):c.6551A>T(p.Asn2184Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,613,848 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).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.33

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 -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBN2
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.099175304).
• BP6: Variant 5-128289213-T-A is Benign according to our data. Variant chr5-128289213-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210998.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00157 (239/152312) while in subpopulation AFR AF= 0.00522 (217/41562). AF 95% confidence interval is 0.00465. There are 1 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 238 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.6551A>T	p.Asn2184Ile	missense_variant	52/65	ENST00000262464.9
FBN2	XM_017009228.3	c.6398A>T	p.Asn2133Ile	missense_variant	51/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.6551A>T	p.Asn2184Ile	missense_variant	52/65	1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.3335A>T		non_coding_transcript_exon_variant	27/38
FBN2	ENST00000703785.1	n.3254A>T		non_coding_transcript_exon_variant	26/27

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000375 AC: 94 AN: 250842 Hom.: 1 AF XY: 0.000295 AC XY: 40 AN XY: 135608

Gnomad AFR exome AF: 0.00475

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000194 AC: 284 AN: 1461536 Hom.: 0 Cov.: 31 AF XY: 0.000179 AC XY: 130 AN XY: 727078

Gnomad4 AFR exome AF: 0.00553

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74478

Gnomad4 AFR AF: 0.00522

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000346 Hom.: 0

Bravo AF: 0.00192

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 24, 2015	- -

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2016

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;.;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.;.
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.099	T;T;T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.3	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.3	D;.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;.;D
Polyphen		0.98	D;.;D
Vest4		0.82
MVP		0.92
MPC		0.73
ClinPred		0.11	T
GERP RS		5.8
Varity_R		0.77
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs149071226; hg19: chr5-127624905;