5-128258636-T-C

Position:

• chr5-128258636-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001999.4(FBN2):​c.*819A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 152,680 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.035 (134 hom., cov: 32)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: FBN2 NM_001999.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.475

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 5-128258636-T-C is Benign according to our data. Variant chr5-128258636-T-C is described in ClinVar as [Benign]. Clinvar id is 350739.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.*819A>G		3_prime_UTR_variant	65/65	ENST00000262464.9
FBN2	XM_017009228.3	c.*819A>G		3_prime_UTR_variant	64/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.*819A>G		3_prime_UTR_variant	65/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5262 AN: 152094 Hom.: 134 Cov.: 32

Gnomad AFR AF: 0.00908

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.0293

Gnomad ASJ AF: 0.0672

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0152

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0556

Gnomad OTH AF: 0.0325

GnomAD4 exome AF: 0.0214 AC: 10 AN: 468 Hom.: 0 Cov.: 0 AF XY: 0.0248 AC XY: 7 AN XY: 282

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0346 AC: 5259 AN: 152212 Hom.: 134 Cov.: 32 AF XY: 0.0324 AC XY: 2413 AN XY: 74412

Gnomad4 AFR AF: 0.00905

Gnomad4 AMR AF: 0.0292

Gnomad4 ASJ AF: 0.0672

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0150

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0556

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0480 Hom.: 35

Bravo AF: 0.0351

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.47
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs72783099; hg19: chr5-127594328;