rs10044959

chr5-128312808-A-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.4718-13T>C 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 0.103 in 1,612,828 control chromosomes in the GnomAD database, including 9,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (622 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8944 hom.)
• Consequence: FBN2 NM_001999.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.04

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=-0.59).
• BP6: Variant 5-128312808-A-G is Benign according to our data. Variant chr5-128312808-A-G is described in ClinVar as [Benign]. Clinvar id is 137334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128312808-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.4718-13T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262464.9
FBN2	XM_017009228.3	c.4565-13T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.4718-13T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.1502-13T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
FBN2	ENST00000703785.1	n.1583-855T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0787 AC: 11968 AN: 152152 Hom.: 622 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.0741

Gnomad ASJ AF: 0.0813

Gnomad EAS AF: 0.00675

Gnomad SAS AF: 0.0934

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.0843

GnomAD3 exomes AF: 0.0861 AC: 21547 AN: 250320 Hom.: 1201 AF XY: 0.0901 AC XY: 12196 AN XY: 135344

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.0571

Gnomad ASJ exome AF: 0.0704

Gnomad EAS exome AF: 0.00201

Gnomad SAS exome AF: 0.0986

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.0987

GnomAD4 exome AF: 0.106 AC: 154759 AN: 1460558 Hom.: 8944 Cov.: 32 AF XY: 0.106 AC XY: 77196 AN XY: 726682

Gnomad4 AFR exome AF: 0.0156

Gnomad4 AMR exome AF: 0.0586

Gnomad4 ASJ exome AF: 0.0729

Gnomad4 EAS exome AF: 0.0135

Gnomad4 SAS exome AF: 0.0975

Gnomad4 FIN exome AF: 0.0974

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.0930

GnomAD4 genome AF: 0.0786 AC: 11963 AN: 152270 Hom.: 622 Cov.: 32 AF XY: 0.0781 AC XY: 5813 AN XY: 74444

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.0740

Gnomad4 ASJ AF: 0.0813

Gnomad4 EAS AF: 0.00676

Gnomad4 SAS AF: 0.0937

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.0834

Alfa AF: 0.0941 Hom.: 167

Bravo AF: 0.0723

Asia WGS AF: 0.0420 AC: 145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 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	4718-13T>C in intron 36 of FBN2: This variant is not expected to have clinical s ignificance because it has been identified in 11.8% (1017/8600) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs10044959). -

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

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	13
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs10044959; hg19: chr5-127648500; COSMIC: COSV52493141;