rs17608435

chr5-128289088-T-Cchr5-128289088-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):c.6637+39A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0334 in 1,610,364 control chromosomes in the GnomAD database, including 1,078 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (83 hom., cov: 32)
  • Exomes 𝑓: 0.034 (995 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.38

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-128289088-T-C is Benign according to our data. Variant chr5-128289088-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 258523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128289088-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0281 (4278/152246) while in subpopulation AMR AF= 0.0415 (634/15280). AF 95% confidence interval is 0.0392. There are 83 homozygotes in gnomad4. There are 2038 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 4279 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.6637+39A>G		intron_variant		ENST00000262464.9
FBN2	XM_017009228.3	c.6484+39A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.6637+39A>G		intron_variant		1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.3421+39A>G		intron_variant, non_coding_transcript_variant
FBN2	ENST00000703785.1	n.3340+39A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4279 AN: 152128 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0415

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0397

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0405

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0278 AC: 6948 AN: 249988 Hom.: 151 AF XY: 0.0281 AC XY: 3804 AN XY: 135248

Gnomad AFR exome AF: 0.00663

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.00858

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00739

Gnomad FIN exome AF: 0.0425

Gnomad NFE exome AF: 0.0412

Gnomad OTH exome AF: 0.0378

GnomAD4 exome AF: 0.0339 AC: 49491 AN: 1458118 Hom.: 995 Cov.: 31 AF XY: 0.0333 AC XY: 24201 AN XY: 725682

Gnomad4 AFR exome AF: 0.00587

Gnomad4 AMR exome AF: 0.0232

Gnomad4 ASJ exome AF: 0.00796

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00746

Gnomad4 FIN exome AF: 0.0447

Gnomad4 NFE exome AF: 0.0389

Gnomad4 OTH exome AF: 0.0295

GnomAD4 genome AF: 0.0281 AC: 4278 AN: 152246 Hom.: 83 Cov.: 32 AF XY: 0.0274 AC XY: 2038 AN XY: 74424

Gnomad4 AFR AF: 0.00763

Gnomad4 AMR AF: 0.0415

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0397

Gnomad4 NFE AF: 0.0405

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0274 Hom.: 35

Bravo AF: 0.0259

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.0030
Dann	Benign	0.65

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: rs17608435; hg19: chr5-127624780;