rs557229598

Variant names:

• chr5-128258264-G-A
• rs557229598
• NM_001999.4:c.*1191C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128258264-G-A
• chr5-128258264-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001999.4(FBN2):​c.*1191C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 152,110 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBN2 NM_001999.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.62
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-128258264-G-A is Benign according to our data. Variant chr5-128258264-G-A is described in ClinVar as Benign. ClinVar VariationId is 350733.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00236 (359/152110) while in subpopulation SAS AF = 0.0052 (25/4804). AF 95% confidence interval is 0.00379. There are 1 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 359 AD,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.*1191C>T		3_prime_UTR	Exon 65 of 65	NP_001990.2	P35556-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.*1191C>T		3_prime_UTR	Exon 65 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.*1191C>T		3_prime_UTR	Exon 64 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.*1191C>T		3_prime_UTR	Exon 64 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 151992 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00520

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.000479

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152110 Hom.: 1 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74360

African (AFR) AF: 0.000844 AC: 35 AN: 41486

American (AMR) AF: 0.000458 AC: 7 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00520 AC: 25 AN: 4804

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00419 AC: 285 AN: 68000

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.00219

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital contractural arachnodactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.87
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs557229598; hg19: chr5-127593956;