rs17608435

Variant names:

• chr5-128289088-T-C
• rs17608435
• NM_001999.4:c.6637+39A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-128289088-T-C
• chr5-128289088-T-G

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -5.38
• Publications: 3 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=-0.88).
• BP6: Variant 5-128289088-T-C is Benign according to our data. Variant chr5-128289088-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4278 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6637+39A>G		intron_variant	Intron 52 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6484+39A>G		intron_variant	Intron 51 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6637+39A>G		intron_variant	Intron 52 of 64	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3421+39A>G		intron_variant	Intron 27 of 37
FBN2	ENST00000703785.1	n.3340+39A>G		intron_variant	Intron 26 of 26

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

GnomAD2 exomes AF: 0.0278 AC: 6948 AN: 249988 AF XY: 0.0281

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 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

African (AFR) AF: 0.00587 AC: 196 AN: 33404

American (AMR) AF: 0.0232 AC: 1038 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00796 AC: 208 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00746 AC: 643 AN: 86208

European-Finnish (FIN) AF: 0.0447 AC: 2385 AN: 53326

Middle Eastern (MID) AF: 0.0203 AC: 117 AN: 5752

European-Non Finnish (NFE) AF: 0.0389 AC: 43129 AN: 1108688

Other (OTH) AF: 0.0295 AC: 1775 AN: 60248

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

African (AFR) AF: 0.00763 AC: 317 AN: 41552

American (AMR) AF: 0.0415 AC: 634 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4830

European-Finnish (FIN) AF: 0.0397 AC: 421 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0405 AC: 2752 AN: 68016

Other (OTH) AF: 0.0289 AC: 61 AN: 2112

Alfa AF: 0.0281 Hom.: 45

Bravo AF: 0.0259

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.88
CADD	Benign	0.0030
DANN	Benign	0.65
PhyloP100		-5.4
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: rs17608435; hg19: chr5-127624780;