rs28763952

Variant names:

• chr5-128392160-G-A
• rs28763952
• NM_001999.4:c.1466-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128392160-G-A
• chr5-128392160-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):​c.1466-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,612,352 control chromosomes in the GnomAD database, including 39 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 0.0082 (17 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (22 hom.)
• Consequence: FBN2 NM_001999.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003805
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.102
• Publications: 2 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• familial thoracic aortic aneurysm and aortic dissection

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-128392160-G-A is Benign according to our data. Variant chr5-128392160-G-A is described in ClinVar as Benign. ClinVar VariationId is 129035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00818 (1245/152122) while in subpopulation AFR AF = 0.0283 (1174/41508). AF 95% confidence interval is 0.0269. There are 17 homozygotes in GnomAd4. There are 586 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1245 AD gene.

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.1466-5C>T		splice_region intron	N/A	NP_001990.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.1466-5C>T		splice_region intron	N/A	ENSP00000262464.4
	FBN2	ENST00000939405.1		c.1367-5C>T		splice_region intron	N/A	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.1313-5C>T		splice_region intron	N/A	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.00811 AC: 1232 AN: 152004 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00217 AC: 544 AN: 250804 AF XY: 0.00153

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000947 AC: 1383 AN: 1460230 Hom.: 22 Cov.: 30 AF XY: 0.000862 AC XY: 626 AN XY: 726496

African (AFR) AF: 0.0302 AC: 1010 AN: 33422

American (AMR) AF: 0.00125 AC: 56 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39612

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5756

European-Non Finnish (NFE) AF: 0.000115 AC: 128 AN: 1110812

Other (OTH) AF: 0.00224 AC: 135 AN: 60336

GnomAD4 genome AF: 0.00818 AC: 1245 AN: 152122 Hom.: 17 Cov.: 33 AF XY: 0.00788 AC XY: 586 AN XY: 74360

African (AFR) AF: 0.0283 AC: 1174 AN: 41508

American (AMR) AF: 0.00275 AC: 42 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67992

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00461 Hom.: 5

Bravo AF: 0.00908

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Congenital contractural arachnodactyly (2)
-	-	2	not provided (2)
-	-	1	Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.54
PhyloP100		-0.10
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.068
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: rs28763952; hg19: chr5-127727853; COSMIC: COSV52540635;