rs375666281

chr5-128361741-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001999.4(FBN2):c.2536G>A(p.Glu846Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00021 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E846E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 4.99

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 -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.26250064).
• BP6: Variant 5-128361741-C-T is Benign according to our data. Variant chr5-128361741-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213392.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}. Variant chr5-128361741-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000151 (23/152220) while in subpopulation NFE AF= 0.000309 (21/68032). AF 95% confidence interval is 0.000207. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.2536G>A	p.Glu846Lys	missense_variant	19/65	ENST00000262464.9
FBN2	XM_017009228.3	c.2383G>A	p.Glu795Lys	missense_variant	18/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.2536G>A	p.Glu846Lys	missense_variant	19/65	1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.2437G>A	p.Glu813Lys	missense_variant	18/33	2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251432 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000299

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000216 AC: 316 AN: 1461830 Hom.: 0 Cov.: 32 AF XY: 0.000199 AC XY: 145 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000279

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74374

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 29, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2022	Identified in a patient with features of Marfan syndrome who was incidentally diagnosed with subclinical tuberous sclerosis complex when a maternally inherited TSC1 variant was identified through whole exome sequencing (Caylor et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not substitute or introduce a cysteine residue (Callewaert et al., 2009; Frederic et al., 2009); Not located within exons 24-33, where the majority of pathogenic variants reported to date occur (Callewaert et al., 2009, Frederic et al., 2009); This variant is associated with the following publications: (PMID: 29926239, 19006240, 18767143) -

Congenital contractural arachnodactyly Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2021

The p.E846K variant (also known as c.2536G>A), located in coding exon 19 of the FBN2 gene, results from a G to A substitution at nucleotide position 2536. The glutamic acid at codon 846 is replaced by lysine, an amino acid with similar properties. This alteration was reported in a patient with suspicion of Marfan syndrome, but this variant was not thought to be responsible for the clinical phenotype (Caylor RC et al. Neurogenetics, 2018 Aug;19(3):205-213). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

FBN2 NM_001999.3 exon 19 p.Glu846Lys (c.2536G>A): This variant has not been reported in the literature but is present in 0.02% (37/129150) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-127697434-C-T). This variant is present in ClinVar (Variation ID:213392). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;.;T;D
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;.;.;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Benign	0.57	N;.;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N;.;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.090	T;.;T;T
Polyphen		0.65	P;.;P;P
Vest4		0.43
MVP		0.32
MPC		0.53
ClinPred		0.29	T
GERP RS		4.8
Varity_R		0.19
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs375666281; hg19: chr5-127697434;