rs201818403

chr5-128408807-A-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):c.953-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,613,750 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: FBN2 NM_001999.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.006654
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.79

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 5-128408807-A-C is Benign according to our data. Variant chr5-128408807-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 137315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128408807-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00144 (219/152186) while in subpopulation NFE AF= 0.00191 (130/68034). AF 95% confidence interval is 0.00164. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.953-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262464.9
FBN2	XM_017009228.3	c.953-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.953-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001999.4	P1
FBN2	ENST00000508053.6	c.953-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
FBN2	ENST00000508989.5	c.854-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2
FBN2	ENST00000703787.1	n.660-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00168 AC: 421 AN: 250908 Hom.: 3 AF XY: 0.00170 AC XY: 231 AN XY: 135590

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00180 AC: 2627 AN: 1461564 Hom.: 3 Cov.: 31 AF XY: 0.00178 AC XY: 1291 AN XY: 727102

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00191

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74354

Gnomad4 AFR AF: 0.000627

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00191

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00250 Hom.: 1

Bravo AF: 0.00145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital contractural arachnodactyly Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 11, 2016	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Mar 09, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Mar 20, 2015	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FBN2: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Connective tissue disorder Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Feb 01, 2020	- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	14
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0067
dbscSNV1_RF	Benign	0.23
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: rs201818403; hg19: chr5-127744500;