rs2042327

chr5-128287291-C-T

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.6880+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,612,308 control chromosomes in the GnomAD database, including 247,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (18921 hom., cov: 32)
  • Exomes 𝑓: 0.55 (228610 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.804

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=-0.83).
• BP6: Variant 5-128287291-C-T is Benign according to our data. Variant chr5-128287291-C-T is described in ClinVar as [Benign]. Clinvar id is 137347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128287291-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.6880+17G>A		intron_variant		ENST00000262464.9
FBN2	XM_017009228.3	c.6727+17G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.6880+17G>A		intron_variant		1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.3664+17G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69575 AN: 151958 Hom.: 18911 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.693

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.488

GnomAD3 exomes AF: 0.523 AC: 131520 AN: 251234 Hom.: 37524 AF XY: 0.533 AC XY: 72426 AN XY: 135772

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.557

Gnomad ASJ exome AF: 0.545

Gnomad EAS exome AF: 0.186

Gnomad SAS exome AF: 0.518

Gnomad FIN exome AF: 0.682

Gnomad NFE exome AF: 0.587

Gnomad OTH exome AF: 0.574

GnomAD4 exome AF: 0.551 AC: 804264 AN: 1460230 Hom.: 228610 Cov.: 36 AF XY: 0.552 AC XY: 401282 AN XY: 726490

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.557

Gnomad4 ASJ exome AF: 0.552

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.520

Gnomad4 FIN exome AF: 0.686

Gnomad4 NFE exome AF: 0.572

Gnomad4 OTH exome AF: 0.517

GnomAD4 genome AF: 0.458 AC: 69588 AN: 152078 Hom.: 18921 Cov.: 32 AF XY: 0.463 AC XY: 34382 AN XY: 74320

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.555

Gnomad4 ASJ AF: 0.552

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.507

Gnomad4 FIN AF: 0.693

Gnomad4 NFE AF: 0.586

Gnomad4 OTH AF: 0.487

Alfa AF: 0.543 Hom.: 15178

Bravo AF: 0.427

Asia WGS AF: 0.391 AC: 1359 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital contractural arachnodactyly Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 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	-	- -

not provided Benign:2

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.6880+17G>A 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 62933/121394 control chromosomes at a frequency of 0.5184194, which is approximately 414735 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), strong evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Macular degeneration, early-onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.81
Dann	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs2042327; hg19: chr5-127622983; COSMIC: COSV52501201;