chr5-128317330-A-C

Variant names:

• chr5-128317330-A-C
• rs10057405
• NM_001999.4:c.4717+819T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001999.4(FBN2):​c.4717+819T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0796 in 152,292 control chromosomes in the GnomAD database, including 627 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.080 (627 hom., cov: 32)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.974
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.4717+819T>G		intron_variant	Intron 36 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.4564+819T>G		intron_variant	Intron 35 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.4717+819T>G		intron_variant	Intron 36 of 64	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.1501+819T>G		intron_variant	Intron 11 of 37
FBN2	ENST00000703785.1	n.1582+819T>G		intron_variant	Intron 11 of 26

Frequencies

GnomAD3 genomes AF: 0.0796 AC: 12119 AN: 152174 Hom.: 627 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0743

Gnomad ASJ AF: 0.0813

Gnomad EAS AF: 0.00692

Gnomad SAS AF: 0.0935

Gnomad FIN AF: 0.0998

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.0848

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0796 AC: 12116 AN: 152292 Hom.: 627 Cov.: 32 AF XY: 0.0790 AC XY: 5884 AN XY: 74454

African (AFR) AF: 0.0249 AC: 1034 AN: 41570

American (AMR) AF: 0.0743 AC: 1135 AN: 15286

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

East Asian (EAS) AF: 0.00693 AC: 36 AN: 5194

South Asian (SAS) AF: 0.0938 AC: 453 AN: 4830

European-Finnish (FIN) AF: 0.0998 AC: 1059 AN: 10606

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

European-Non Finnish (NFE) AF: 0.115 AC: 7826 AN: 68020

Other (OTH) AF: 0.0839 AC: 177 AN: 2110

Alfa AF: 0.0997 Hom.: 2124

Bravo AF: 0.0732

Asia WGS AF: 0.0420 AC: 146 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.67
PhyloP100		0.97
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: rs10057405; hg19: chr5-127653022; COSMIC: COSV52501287;