5-128536502-G-T

Variant names:

• chr5-128536502-G-T
• rs200300875
• NM_001999.4:c.255-18C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000262464.9(FBN2):​c.255-18C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000975 in 1,601,448 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (17 hom.)
• Consequence: FBN2 ENST00000262464.9 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.114
• Publications: 0 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=-0.66).
• BP6: Variant 5-128536502-G-T is Benign according to our data. Variant chr5-128536502-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00115 (175/152188) while in subpopulation NFE AF = 0.000397 (27/68026). AF 95% confidence interval is 0.00028. There are 2 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 175 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262464.9. 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.255-18C>A		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.255-18C>A		intron	N/A	ENSP00000262464.4
	FBN2	ENST00000502468.5	TSL:1	c.255-18C>A		intron	N/A	ENSP00000424753.1
	FBN2	ENST00000508989.5	TSL:2	c.255-18C>A		intron	N/A	ENSP00000425596.1

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152188 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00174 AC: 423 AN: 243502 AF XY: 0.00162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0373

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000401

Gnomad OTH exome AF: 0.00202

GnomAD4 exome AF: 0.000957 AC: 1387 AN: 1449260 Hom.: 17 Cov.: 29 AF XY: 0.00102 AC XY: 737 AN XY: 721262

African (AFR) AF: 0.00 AC: 0 AN: 33252

American (AMR) AF: 0.0000226 AC: 1 AN: 44290

Ashkenazi Jewish (ASJ) AF: 0.0378 AC: 980 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53150

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.000207 AC: 228 AN: 1101974

Other (OTH) AF: 0.00289 AC: 173 AN: 59944

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152188 Hom.: 2 Cov.: 32 AF XY: 0.000955 AC XY: 71 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 140 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68026

Other (OTH) AF: 0.00287 AC: 6 AN: 2092

Alfa AF: 0.00508 Hom.: 3

Bravo AF: 0.00132

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Congenital contractural arachnodactyly (1)
-	-	1	Connective tissue disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.0
DANN	Benign	0.85
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs200300875; hg19: chr5-127872195; COSMIC: COSV52490284; COSMIC: COSV52490284;