chr5-128312808-A-G

Variant names:

• chr5-128312808-A-G
• rs10044959
• NM_001999.4:c.4718-13T>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.4718-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,612,828 control chromosomes in the GnomAD database, including 9,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (622 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8944 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.04
• Publications: 8 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=-0.59).
• BP6: Variant 5-128312808-A-G is Benign according to our data. Variant chr5-128312808-A-G is described in ClinVar as Benign. ClinVar VariationId is 137334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 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.4718-13T>C		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.4718-13T>C		intron	N/A	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.4619-13T>C		intron	N/A	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.4565-13T>C		intron	N/A	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.0787 AC: 11968 AN: 152152 Hom.: 622 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.0741

Gnomad ASJ AF: 0.0813

Gnomad EAS AF: 0.00675

Gnomad SAS AF: 0.0934

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.0843

GnomAD2 exomes AF: 0.0861 AC: 21547 AN: 250320 AF XY: 0.0901

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.0571

Gnomad ASJ exome AF: 0.0704

Gnomad EAS exome AF: 0.00201

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.0987

GnomAD4 exome AF: 0.106 AC: 154759 AN: 1460558 Hom.: 8944 Cov.: 32 AF XY: 0.106 AC XY: 77196 AN XY: 726682

African (AFR) AF: 0.0156 AC: 521 AN: 33474

American (AMR) AF: 0.0586 AC: 2622 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 1904 AN: 26134

East Asian (EAS) AF: 0.0135 AC: 537 AN: 39700

South Asian (SAS) AF: 0.0975 AC: 8410 AN: 86250

European-Finnish (FIN) AF: 0.0974 AC: 5121 AN: 52582

Middle Eastern (MID) AF: 0.0840 AC: 484 AN: 5764

European-Non Finnish (NFE) AF: 0.117 AC: 129543 AN: 1111562

Other (OTH) AF: 0.0930 AC: 5617 AN: 60368

GnomAD4 genome AF: 0.0786 AC: 11963 AN: 152270 Hom.: 622 Cov.: 32 AF XY: 0.0781 AC XY: 5813 AN XY: 74444

African (AFR) AF: 0.0215 AC: 894 AN: 41572

American (AMR) AF: 0.0740 AC: 1132 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0813 AC: 282 AN: 3470

East Asian (EAS) AF: 0.00676 AC: 35 AN: 5174

South Asian (SAS) AF: 0.0937 AC: 452 AN: 4826

European-Finnish (FIN) AF: 0.100 AC: 1064 AN: 10612

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7814 AN: 68010

Other (OTH) AF: 0.0834 AC: 176 AN: 2110

Alfa AF: 0.0941 Hom.: 167

Bravo AF: 0.0723

Asia WGS AF: 0.0420 AC: 145 AN: 3478

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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		3.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs10044959; hg19: chr5-127648500; COSMIC: COSV52493141;