NM_001999.4:c.6758-48T>C

Variant names:

• chr5-128287478-A-G
• rs42688
• NM_001999.4:c.6758-48T>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.6758-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.075 in 1,608,032 control chromosomes in the GnomAD database, including 12,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2073 hom., cov: 32)
  • Exomes 𝑓: 0.071 (10591 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0300
• 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=-0.82).
• BP6: Variant 5-128287478-A-G is Benign according to our data. Variant chr5-128287478-A-G is described in ClinVar as Benign. ClinVar VariationId is 258524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6758-48T>C		intron_variant	Intron 53 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6605-48T>C		intron_variant	Intron 52 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6758-48T>C		intron_variant	Intron 53 of 64	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3542-48T>C		intron_variant	Intron 28 of 37

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17710 AN: 152068 Hom.: 2070 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0675

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.601

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0500

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0870

GnomAD2 exomes AF: 0.112 AC: 27834 AN: 248304 AF XY: 0.109

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.0409

Gnomad ASJ exome AF: 0.0563

Gnomad EAS exome AF: 0.630

Gnomad FIN exome AF: 0.0527

Gnomad NFE exome AF: 0.0453

Gnomad OTH exome AF: 0.0720

GnomAD4 exome AF: 0.0706 AC: 102840 AN: 1455846 Hom.: 10591 Cov.: 30 AF XY: 0.0718 AC XY: 51979 AN XY: 724414

African (AFR) AF: 0.214 AC: 7112 AN: 33298

American (AMR) AF: 0.0417 AC: 1863 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0580 AC: 1510 AN: 26054

East Asian (EAS) AF: 0.602 AC: 23794 AN: 39522

South Asian (SAS) AF: 0.136 AC: 11678 AN: 85994

European-Finnish (FIN) AF: 0.0514 AC: 2723 AN: 52992

Middle Eastern (MID) AF: 0.0386 AC: 222 AN: 5750

European-Non Finnish (NFE) AF: 0.0442 AC: 48902 AN: 1107486

Other (OTH) AF: 0.0838 AC: 5036 AN: 60104

GnomAD4 genome AF: 0.117 AC: 17735 AN: 152186 Hom.: 2073 Cov.: 32 AF XY: 0.121 AC XY: 9011 AN XY: 74404

African (AFR) AF: 0.214 AC: 8873 AN: 41506

American (AMR) AF: 0.0672 AC: 1028 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 179 AN: 3468

East Asian (EAS) AF: 0.601 AC: 3097 AN: 5154

South Asian (SAS) AF: 0.150 AC: 723 AN: 4814

European-Finnish (FIN) AF: 0.0500 AC: 531 AN: 10614

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0457 AC: 3106 AN: 68016

Other (OTH) AF: 0.0894 AC: 189 AN: 2114

Alfa AF: 0.0653 Hom.: 257

Bravo AF: 0.122

Asia WGS AF: 0.313 AC: 1087 AN: 3476

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	-0.82
CADD	Benign	2.8
DANN	Benign	0.48
PhyloP100		0.030
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: rs42688; hg19: chr5-127623170; COSMIC: COSV107281716;