rs28763927

Variant names:

• chr5-128280322-A-G
• rs28763927
• NM_001999.4:c.7013-5T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001999.4(FBN2):​c.7013-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 1,604,704 control chromosomes in the GnomAD database, including 4,846 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (450 hom., cov: 33)
  • Exomes 𝑓: 0.075 (4396 hom.)
• Consequence: FBN2 NM_001999.4 splice_region, intron
• Scores: Splicing: ADA: 0.0007284
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.272
• Publications: 7 publications found

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]

FBN2 Gene-Disease associations (from GenCC):

• congenital contractural arachnodactyly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-128280322-A-G is Benign according to our data. Variant chr5-128280322-A-G is described in ClinVar as Benign. ClinVar VariationId is 129048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0941 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.7013-5T>C		splice_region intron	N/A	NP_001990.2	P35556-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.7013-5T>C		splice_region intron	N/A	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.6914-5T>C		splice_region intron	N/A	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.6860-5T>C		splice_region intron	N/A	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.0709 AC: 10789 AN: 152122 Hom.: 450 Cov.: 33

Gnomad AFR AF: 0.0776

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0660

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.0631

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0344

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0724

Gnomad OTH AF: 0.0708

GnomAD2 exomes AF: 0.0749 AC: 18758 AN: 250328 AF XY: 0.0757

Gnomad AFR exome AF: 0.0808

Gnomad AMR exome AF: 0.0808

Gnomad ASJ exome AF: 0.0702

Gnomad EAS exome AF: 0.0606

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0744

Gnomad OTH exome AF: 0.0716

GnomAD4 exome AF: 0.0752 AC: 109262 AN: 1452464 Hom.: 4396 Cov.: 28 AF XY: 0.0760 AC XY: 54954 AN XY: 723088

African (AFR) AF: 0.0754 AC: 2511 AN: 33284

American (AMR) AF: 0.0778 AC: 3477 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0673 AC: 1754 AN: 26080

East Asian (EAS) AF: 0.0615 AC: 2433 AN: 39530

South Asian (SAS) AF: 0.0992 AC: 8536 AN: 86062

European-Finnish (FIN) AF: 0.0435 AC: 2297 AN: 52830

Middle Eastern (MID) AF: 0.120 AC: 686 AN: 5740

European-Non Finnish (NFE) AF: 0.0750 AC: 82813 AN: 1104192

Other (OTH) AF: 0.0792 AC: 4755 AN: 60056

GnomAD4 genome AF: 0.0708 AC: 10786 AN: 152240 Hom.: 450 Cov.: 33 AF XY: 0.0690 AC XY: 5137 AN XY: 74446

African (AFR) AF: 0.0776 AC: 3222 AN: 41540

American (AMR) AF: 0.0660 AC: 1009 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3470

East Asian (EAS) AF: 0.0625 AC: 324 AN: 5186

South Asian (SAS) AF: 0.102 AC: 490 AN: 4826

European-Finnish (FIN) AF: 0.0344 AC: 365 AN: 10602

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0724 AC: 4921 AN: 68000

Other (OTH) AF: 0.0705 AC: 149 AN: 2112

Alfa AF: 0.0597 Hom.: 158

Bravo AF: 0.0730

Asia WGS AF: 0.0710 AC: 249 AN: 3476

EpiCase AF: 0.0740

EpiControl AF: 0.0760

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Congenital contractural arachnodactyly (2)
-	-	2	not provided (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.4
DANN	Benign	0.76
PhyloP100		0.27
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00073
dbscSNV1_RF	Benign	0.050
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

Other links and lift over

dbSNP: rs28763927; hg19: chr5-127616014; COSMIC: COSV52516898;