rs1050687

Variant names:

• chr5-128258040-C-T
• rs1050687
• NM_001999.4:c.*1415G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001999.4(FBN2):​c.*1415G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 151,806 control chromosomes in the GnomAD database, including 7,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (7980 hom., cov: 32)
  • Exomes 𝑓: 0.16 (4 hom.)
• Consequence: FBN2 NM_001999.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.390
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-128258040-C-T is Benign according to our data. Variant chr5-128258040-C-T is described in ClinVar as Benign. ClinVar VariationId is 350729.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.58 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.*1415G>A		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.*1415G>A		3_prime_UTR	Exon 65 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.*1415G>A		3_prime_UTR	Exon 64 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.*1415G>A		3_prime_UTR	Exon 64 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37556 AN: 151268 Hom.: 7949 Cov.: 32

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.0755

Gnomad EAS AF: 0.0401

Gnomad SAS AF: 0.0720

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.198

GnomAD4 exome AF: 0.164 AC: 71 AN: 432 Hom.: 4 Cov.: 0 AF XY: 0.185 AC XY: 48 AN XY: 260

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.164 AC: 70 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

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

Other (OTH) AF: 0.250 AC: 1 AN: 4

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.249 AC: 37636 AN: 151374 Hom.: 7980 Cov.: 32 AF XY: 0.244 AC XY: 18049 AN XY: 73952

African (AFR) AF: 0.586 AC: 24097 AN: 41092

American (AMR) AF: 0.139 AC: 2112 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0755 AC: 262 AN: 3470

East Asian (EAS) AF: 0.0404 AC: 209 AN: 5170

South Asian (SAS) AF: 0.0718 AC: 346 AN: 4818

European-Finnish (FIN) AF: 0.145 AC: 1512 AN: 10422

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8542 AN: 67846

Other (OTH) AF: 0.195 AC: 410 AN: 2102

Alfa AF: 0.230 Hom.: 2953

Bravo AF: 0.264

Asia WGS AF: 0.0910 AC: 317 AN: 3472

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	-0.92
CADD	Benign	0.21
DANN	Benign	0.34
PhyloP100		0.39
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: rs1050687; hg19: chr5-127593732; COSMIC: COSV52536600;