rs56025995

Positions:

• chr5-128464930-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000262464.9(FBN2):​c.629-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 1,613,962 control chromosomes in the GnomAD database, including 619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (55 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (564 hom.)
• Consequence: FBN2 ENST00000262464.9 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0006589
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0510

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 5-128464930-T-C is Benign according to our data. Variant chr5-128464930-T-C is described in ClinVar as [Benign]. Clinvar id is 129045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128464930-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.629-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.629-9A>G		splice_polypyrimidine_tract_variant, intron_variant			XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.629-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001999.4	ENSP00000262464	P1

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 1002 AN: 152212 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.0218 AC: 5491 AN: 251412 Hom.: 488 AF XY: 0.0157 AC XY: 2140 AN XY: 135900

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0145

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.00492 AC: 7198 AN: 1461632 Hom.: 564 Cov.: 31 AF XY: 0.00409 AC XY: 2974 AN XY: 727150

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0182

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.00414

GnomAD4 genome AF: 0.00664 AC: 1012 AN: 152330 Hom.: 55 Cov.: 32 AF XY: 0.00681 AC XY: 507 AN XY: 74486

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.0536

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0162

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00242 Hom.: 8

Bravo AF: 0.0139

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	629-9A>G in intron 5 of FBN2: This variant is not expected to have clinical sign ificance because it has been identified in 13.6% (18/132) of Mexican chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.go v/projects/SNP; dbSNP rs56025995). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 27, 2023	Variant summary: FBN2 c.629-9A>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.022 in 251412 control chromosomes, predominantly at a frequency of 0.15 within the Latino subpopulation in the gnomAD database, including 481 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 120,000-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 Latino origin. To our knowledge, no occurrence of c.629-9A>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 22, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 11, 2023

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00066
dbscSNV1_RF	Benign	0.010
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

Publications

LitVar

Other links and lift over

dbSNP: rs56025995; hg19: chr5-127800623;