chr5-128305169-A-G

Variant names:

• chr5-128305169-A-G
• rs27855
• NM_001999.4:c.5675-87T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001999.4(FBN2):​c.5675-87T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,132,668 control chromosomes in the GnomAD database, including 196,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.50 (22235 hom., cov: 33)
  • Exomes 𝑓: 0.59 (174468 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.51
• Publications: 15 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=-0.34).
• BP6: Variant 5-128305169-A-G is Benign according to our data. Variant chr5-128305169-A-G is described in ClinVar as Benign. ClinVar VariationId is 671004.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.5675-87T>C		intron	N/A	NP_001990.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.5675-87T>C		intron	N/A	ENSP00000262464.4
	FBN2	ENST00000939405.1		c.5576-87T>C		intron	N/A	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.5522-87T>C		intron	N/A	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76318 AN: 151976 Hom.: 22225 Cov.: 33

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.520

GnomAD4 exome AF: 0.588 AC: 576900 AN: 980574 Hom.: 174468 AF XY: 0.593 AC XY: 297342 AN XY: 501322

African (AFR) AF: 0.183 AC: 4233 AN: 23096

American (AMR) AF: 0.578 AC: 20208 AN: 34948

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 13424 AN: 22538

East Asian (EAS) AF: 0.812 AC: 27407 AN: 33750

South Asian (SAS) AF: 0.645 AC: 45159 AN: 70050

European-Finnish (FIN) AF: 0.712 AC: 34392 AN: 48316

Middle Eastern (MID) AF: 0.591 AC: 2678 AN: 4534

European-Non Finnish (NFE) AF: 0.579 AC: 404615 AN: 699212

Other (OTH) AF: 0.562 AC: 24784 AN: 44130

GnomAD4 genome AF: 0.502 AC: 76341 AN: 152094 Hom.: 22235 Cov.: 33 AF XY: 0.513 AC XY: 38115 AN XY: 74328

African (AFR) AF: 0.189 AC: 7840 AN: 41514

American (AMR) AF: 0.590 AC: 9008 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2050 AN: 3470

East Asian (EAS) AF: 0.805 AC: 4167 AN: 5176

South Asian (SAS) AF: 0.649 AC: 3131 AN: 4822

European-Finnish (FIN) AF: 0.711 AC: 7507 AN: 10562

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.601 AC: 40852 AN: 67970

Other (OTH) AF: 0.524 AC: 1104 AN: 2108

Alfa AF: 0.574 Hom.: 113136

Bravo AF: 0.472

Asia WGS AF: 0.696 AC: 2416 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.79
PhyloP100		2.5
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: rs27855; hg19: chr5-127640861;