rs56131649

chr5-128289867-T-Cchr5-128289867-T-G

Variant summary

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

The NM_001999.4(FBN2):c.6511+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,475,690 control chromosomes in the GnomAD database, including 20,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1909 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18392 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.37

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=-0.81).
• BP6: Variant 5-128289867-T-C is Benign according to our data. Variant chr5-128289867-T-C is described in ClinVar as [Benign]. Clinvar id is 137345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128289867-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.6511+15A>G		intron_variant		ENST00000262464.9
FBN2	XM_017009228.3	c.6358+15A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.6511+15A>G		intron_variant		1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.3295+15A>G		intron_variant, non_coding_transcript_variant
FBN2	ENST00000703785.1	n.3214+15A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21759 AN: 151968 Hom.: 1901 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.145

GnomAD3 exomes AF: 0.179 AC: 44026 AN: 246426 Hom.: 4584 AF XY: 0.176 AC XY: 23478 AN XY: 133322

Gnomad AFR exome AF: 0.0514

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.156

Gnomad SAS exome AF: 0.180

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.160 AC: 212230 AN: 1323604 Hom.: 18392 Cov.: 20 AF XY: 0.161 AC XY: 107242 AN XY: 666080

Gnomad4 AFR exome AF: 0.0483

Gnomad4 AMR exome AF: 0.288

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.221

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.143 AC: 21780 AN: 152086 Hom.: 1909 Cov.: 32 AF XY: 0.148 AC XY: 10968 AN XY: 74332

Gnomad4 AFR AF: 0.0531

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.150

Alfa AF: 0.149 Hom.: 543

Bravo AF: 0.137

Asia WGS AF: 0.228 AC: 791 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2012	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	6511+15A>G in intron 51 of FBN2: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 16.1% (1383/8594) of European American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs56131649). -

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 22, 2017

Variant summary: The FBN2 c.6511+15A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been observed in a large, broad control population, ExAC, in 20207/102662 control chromosomes (2001 homozygotes) at a frequency of 0.1968, which is approximately 157463 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. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.020
Dann	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs56131649; hg19: chr5-127625559; COSMIC: COSV52511082;