rs112666443

chr5-128305090-AG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001999.4(FBN2):c.5675-9del 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 0.00892 in 1,569,628 control chromosomes in the GnomAD database, including 1,052 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (571 hom., cov: 31)
  • Exomes 𝑓: 0.0049 (481 hom.)
• Consequence: FBN2 NM_001999.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.918

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 -16 ACMG points.

• BP6: Variant 5-128305090-AG-A is Benign according to our data. Variant chr5-128305090-AG-A is described in ClinVar as [Benign]. Clinvar id is 213239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128305090-AG-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.5675-9del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262464.9
FBN2	XM_017009228.3	c.5522-9del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.5675-9del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.2459-9del		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
FBN2	ENST00000703785.1	n.2378-9del		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 7022 AN: 151574 Hom.: 570 Cov.: 31

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.0370

GnomAD3 exomes AF: 0.0152 AC: 2933 AN: 192500 Hom.: 239 AF XY: 0.0113 AC XY: 1160 AN XY: 102572

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00219

Gnomad SAS exome AF: 0.000685

Gnomad FIN exome AF: 0.000256

Gnomad NFE exome AF: 0.000607

Gnomad OTH exome AF: 0.00729

GnomAD4 exome AF: 0.00490 AC: 6952 AN: 1417940 Hom.: 481 Cov.: 29 AF XY: 0.00422 AC XY: 2979 AN XY: 706216

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.00144

Gnomad4 SAS exome AF: 0.000511

Gnomad4 FIN exome AF: 0.0000759

Gnomad4 NFE exome AF: 0.000459

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0464 AC: 7043 AN: 151688 Hom.: 571 Cov.: 31 AF XY: 0.0459 AC XY: 3405 AN XY: 74174

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0187

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000427

Gnomad4 OTH AF: 0.0366

Alfa AF: 0.00395 Hom.: 4

Bravo AF: 0.0515

Asia WGS AF: 0.00838 AC: 30 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 16, 2015	c.5675-9delC in intron 44 of FBN2: This variant is not expected to have clinical significance because it has been identified in 23% (1548/6764) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs112666443). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant was found in TAADV2-PANCARD,TAAD,TAADV2-1 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

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: rs112666443; hg19: chr5-127640782;