rs10519991

chr5-128361896-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.2429-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0865 in 1,576,632 control chromosomes in the GnomAD database, including 6,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (448 hom., cov: 32)
  • Exomes 𝑓: 0.089 (5946 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0880

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=-0.88).
• BP6: Variant 5-128361896-A-G is Benign according to our data. Variant chr5-128361896-A-G is described in ClinVar as [Benign]. Clinvar id is 258512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0934 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.2429-48T>C		intron_variant		ENST00000262464.9
FBN2	XM_017009228.3	c.2276-48T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.2429-48T>C		intron_variant		1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.2330-48T>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0680 AC: 10349 AN: 152150 Hom.: 449 Cov.: 32

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.0540

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.0643

Gnomad SAS AF: 0.0494

Gnomad FIN AF: 0.0944

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0954

Gnomad OTH AF: 0.0679

GnomAD3 exomes AF: 0.0729 AC: 18325 AN: 251232 Hom.: 778 AF XY: 0.0736 AC XY: 9998 AN XY: 135788

Gnomad AFR exome AF: 0.0230

Gnomad AMR exome AF: 0.0416

Gnomad ASJ exome AF: 0.0454

Gnomad EAS exome AF: 0.0582

Gnomad SAS exome AF: 0.0448

Gnomad FIN exome AF: 0.0954

Gnomad NFE exome AF: 0.0976

Gnomad OTH exome AF: 0.0753

GnomAD4 exome AF: 0.0885 AC: 126077 AN: 1424364 Hom.: 5946 Cov.: 25 AF XY: 0.0871 AC XY: 61932 AN XY: 711044

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.0434

Gnomad4 ASJ exome AF: 0.0452

Gnomad4 EAS exome AF: 0.0508

Gnomad4 SAS exome AF: 0.0456

Gnomad4 FIN exome AF: 0.0954

Gnomad4 NFE exome AF: 0.0981

Gnomad4 OTH exome AF: 0.0838

GnomAD4 genome AF: 0.0679 AC: 10344 AN: 152268 Hom.: 448 Cov.: 32 AF XY: 0.0663 AC XY: 4935 AN XY: 74438

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.0539

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.0642

Gnomad4 SAS AF: 0.0488

Gnomad4 FIN AF: 0.0944

Gnomad4 NFE AF: 0.0953

Gnomad4 OTH AF: 0.0676

Alfa AF: 0.0849 Hom.: 362

Bravo AF: 0.0644

Asia WGS AF: 0.0640 AC: 221 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.39
Dann	Benign	0.31

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: rs10519991; hg19: chr5-127697589; COSMIC: COSV52500502; COSMIC: COSV52500502;