NM_001999.4:c.6931A>G

Variant names:

• chr5-128286799-T-C
• rs32209
• NM_001999.4:c.6931A>G

Variant summary

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

Score: -20 - Benign

-20

BP4_StrongBP6_Very_StrongBA1

The NM_001999.4(FBN2):​c.6931A>G​(p.Met2311Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,613,694 control chromosomes in the GnomAD database, including 12,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2077 hom., cov: 33)
  • Exomes 𝑓: 0.071 (10631 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.82
• Publications: 26 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4686584E-4).
• BP6: Variant 5-128286799-T-C is Benign according to our data. Variant chr5-128286799-T-C is described in ClinVar as [Benign]. Clinvar id is 129046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6931A>G	p.Met2311Val	missense_variant	Exon 55 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6778A>G	p.Met2260Val	missense_variant	Exon 54 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6931A>G	p.Met2311Val	missense_variant	Exon 55 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3715A>G		non_coding_transcript_exon_variant	Exon 30 of 38

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17723 AN: 152100 Hom.: 2074 Cov.: 33

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0674

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0875

GnomAD2 exomes AF: 0.112 AC: 28018 AN: 251276 AF XY: 0.109

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.0409

Gnomad ASJ exome AF: 0.0564

Gnomad EAS exome AF: 0.630

Gnomad FIN exome AF: 0.0525

Gnomad NFE exome AF: 0.0453

Gnomad OTH exome AF: 0.0722

GnomAD4 exome AF: 0.0707 AC: 103374 AN: 1461476 Hom.: 10631 Cov.: 32 AF XY: 0.0718 AC XY: 52216 AN XY: 727074

African (AFR) AF: 0.214 AC: 7166 AN: 33462

American (AMR) AF: 0.0418 AC: 1868 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 1514 AN: 26134

East Asian (EAS) AF: 0.602 AC: 23886 AN: 39684

South Asian (SAS) AF: 0.136 AC: 11738 AN: 86246

European-Finnish (FIN) AF: 0.0514 AC: 2745 AN: 53418

Middle Eastern (MID) AF: 0.0387 AC: 223 AN: 5766

European-Non Finnish (NFE) AF: 0.0442 AC: 49166 AN: 1111658

Other (OTH) AF: 0.0839 AC: 5068 AN: 60388

GnomAD4 genome AF: 0.117 AC: 17748 AN: 152218 Hom.: 2077 Cov.: 33 AF XY: 0.121 AC XY: 9022 AN XY: 74416

African (AFR) AF: 0.214 AC: 8880 AN: 41526

American (AMR) AF: 0.0671 AC: 1026 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 179 AN: 3470

East Asian (EAS) AF: 0.602 AC: 3107 AN: 5164

South Asian (SAS) AF: 0.150 AC: 724 AN: 4820

European-Finnish (FIN) AF: 0.0499 AC: 529 AN: 10606

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0456 AC: 3104 AN: 68020

Other (OTH) AF: 0.0899 AC: 190 AN: 2114

Alfa AF: 0.0719 Hom.: 3212

Bravo AF: 0.122

TwinsUK AF: 0.0507 AC: 188

ALSPAC AF: 0.0410 AC: 158

ESP6500AA AF: 0.207 AC: 914

ESP6500EA AF: 0.0416 AC: 358

ExAC AF: 0.115 AC: 13976

Asia WGS AF: 0.313 AC: 1088 AN: 3478

EpiCase AF: 0.0411

EpiControl AF: 0.0442

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Met2311Val in exon 55 of FBN2: This variant is not expected to have clinical sig nificance because it has been identified in 20.7% (914/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs32209). -

Nov 13, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The FBN2 c.6931A>G (p.Met2311Val) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant was found in the large control database ExAC at a frequency of 0.1151322 (13966/121304 control chromosomes [2250 homozygotes]), which is approximately 92106 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Congenital contractural arachnodactyly Benign:2

Jan 13, 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Nov 24, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.21	T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.64	T;.;.
MetaRNN	Benign	0.00015	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.70	N;.;N
PhyloP100		1.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.45	N;.;N
REVEL	Benign	0.28
Sift	Benign	0.43	T;.;T
Polyphen		0.0	B;.;B
Vest4		0.13
MPC		0.24
ClinPred		0.017	T
GERP RS		5.3
Varity_R		0.085
gMVP		0.68
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs32209; hg19: chr5-127622491; COSMIC: COSV52510041;