rs28763934

Variant names:

• chr5-128300793-C-T
• rs28763934
• NM_001999.4:c.6166+24G>A

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.6166+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0979 in 1,610,962 control chromosomes in the GnomAD database, including 8,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (612 hom., cov: 33)
  • Exomes 𝑓: 0.10 (7539 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.135
• Publications: 5 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=-0.72).
• BP6: Variant 5-128300793-C-T is Benign according to our data. Variant chr5-128300793-C-T is described in ClinVar as [Benign]. Clinvar id is 258521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0996 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6166+24G>A		intron_variant	Intron 48 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6013+24G>A		intron_variant	Intron 47 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6166+24G>A		intron_variant	Intron 48 of 64	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.2950+24G>A		intron_variant	Intron 23 of 37
FBN2	ENST00000703785.1	n.2869+24G>A		intron_variant	Intron 22 of 26

Frequencies

GnomAD3 genomes AF: 0.0826 AC: 12556 AN: 152046 Hom.: 612 Cov.: 33

Gnomad AFR AF: 0.0590

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0752

Gnomad ASJ AF: 0.0812

Gnomad EAS AF: 0.0597

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0645

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0820

GnomAD2 exomes AF: 0.0902 AC: 22681 AN: 251358 AF XY: 0.0918

Gnomad AFR exome AF: 0.0596

Gnomad AMR exome AF: 0.0873

Gnomad ASJ exome AF: 0.0852

Gnomad EAS exome AF: 0.0569

Gnomad FIN exome AF: 0.0730

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0890

GnomAD4 exome AF: 0.0995 AC: 145191 AN: 1458798 Hom.: 7539 Cov.: 30 AF XY: 0.100 AC XY: 72668 AN XY: 725904

African (AFR) AF: 0.0539 AC: 1804 AN: 33440

American (AMR) AF: 0.0849 AC: 3795 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0811 AC: 2117 AN: 26108

East Asian (EAS) AF: 0.0614 AC: 2436 AN: 39674

South Asian (SAS) AF: 0.106 AC: 9098 AN: 86200

European-Finnish (FIN) AF: 0.0703 AC: 3751 AN: 53376

Middle Eastern (MID) AF: 0.119 AC: 685 AN: 5754

European-Non Finnish (NFE) AF: 0.104 AC: 115578 AN: 1109252

Other (OTH) AF: 0.0983 AC: 5927 AN: 60280

GnomAD4 genome AF: 0.0825 AC: 12554 AN: 152164 Hom.: 612 Cov.: 33 AF XY: 0.0802 AC XY: 5967 AN XY: 74378

African (AFR) AF: 0.0590 AC: 2450 AN: 41504

American (AMR) AF: 0.0752 AC: 1150 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0812 AC: 282 AN: 3472

East Asian (EAS) AF: 0.0593 AC: 307 AN: 5178

South Asian (SAS) AF: 0.106 AC: 512 AN: 4820

European-Finnish (FIN) AF: 0.0645 AC: 683 AN: 10590

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

European-Non Finnish (NFE) AF: 0.102 AC: 6909 AN: 67994

Other (OTH) AF: 0.0816 AC: 172 AN: 2108

Alfa AF: 0.0961 Hom.: 180

Bravo AF: 0.0813

Asia WGS AF: 0.0740 AC: 259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.6
DANN	Benign	0.74
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28763934; hg19: chr5-127636485; COSMIC: COSV52516931;