5-128537493-C-T

Variant names:

• chr5-128537493-C-T
• rs55715053
• NM_001999.4:c.111G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001999.4(FBN2):​c.111G>A​(p.Pro37Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0919 in 1,584,512 control chromosomes in the GnomAD database, including 8,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P37P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2096 hom., cov: 32)
  • Exomes 𝑓: 0.087 (6394 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.972
• Publications: 8 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• familial thoracic aortic aneurysm and aortic dissection

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 5-128537493-C-T is Benign according to our data. Variant chr5-128537493-C-T is described in ClinVar as Benign. ClinVar VariationId is 129034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.972 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.111G>A	p.Pro37Pro	synonymous_variant	Exon 1 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.111G>A	p.Pro37Pro	synonymous_variant	Exon 1 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.111G>A	p.Pro37Pro	synonymous_variant	Exon 1 of 65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20807 AN: 152076 Hom.: 2080 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0782

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.0778

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0855

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.0882 AC: 17101 AN: 193804 AF XY: 0.0864

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.0596

Gnomad ASJ exome AF: 0.0751

Gnomad EAS exome AF: 0.00170

Gnomad FIN exome AF: 0.0875

Gnomad NFE exome AF: 0.0878

Gnomad OTH exome AF: 0.0865

GnomAD4 exome AF: 0.0871 AC: 124726 AN: 1432318 Hom.: 6394 Cov.: 32 AF XY: 0.0865 AC XY: 61464 AN XY: 710332

African (AFR) AF: 0.289 AC: 9551 AN: 33004

American (AMR) AF: 0.0614 AC: 2522 AN: 41068

Ashkenazi Jewish (ASJ) AF: 0.0733 AC: 1876 AN: 25596

East Asian (EAS) AF: 0.0114 AC: 436 AN: 38296

South Asian (SAS) AF: 0.0852 AC: 7066 AN: 82948

European-Finnish (FIN) AF: 0.0774 AC: 3575 AN: 46196

Middle Eastern (MID) AF: 0.0837 AC: 478 AN: 5710

European-Non Finnish (NFE) AF: 0.0854 AC: 93978 AN: 1100180

Other (OTH) AF: 0.0884 AC: 5244 AN: 59320

GnomAD4 genome AF: 0.137 AC: 20858 AN: 152194 Hom.: 2096 Cov.: 32 AF XY: 0.134 AC XY: 9985 AN XY: 74422

African (AFR) AF: 0.287 AC: 11912 AN: 41520

American (AMR) AF: 0.0780 AC: 1194 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 281 AN: 3470

East Asian (EAS) AF: 0.00522 AC: 27 AN: 5168

South Asian (SAS) AF: 0.0779 AC: 376 AN: 4828

European-Finnish (FIN) AF: 0.0869 AC: 922 AN: 10608

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0854 AC: 5809 AN: 67984

Other (OTH) AF: 0.107 AC: 227 AN: 2112

Alfa AF: 0.0931 Hom.: 274

Bravo AF: 0.141

Asia WGS AF: 0.0610 AC: 212 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Nov 16, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro37Pro in exon 1 of FBN2: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 26.1% (1123/4298) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs55715053). -

Apr 10, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital contractural arachnodactyly Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 27, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.0
DANN	Benign	0.96
PhyloP100		-0.97
PromoterAI		-0.024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs55715053; hg19: chr5-127873186; COSMIC: COSV52505361; COSMIC: COSV52505361;