rs374748

Variant names:

• chr5-128363682-G-A
• rs374748
• NM_001999.4:c.2428+918C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128363682-G-A
• chr5-128363682-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001999.4(FBN2):​c.2428+918C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.856 in 152,156 control chromosomes in the GnomAD database, including 56,305 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.86 (56305 hom., cov: 32)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.80
• Publications: 13 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 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.2428+918C>T		intron	N/A	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.2428+918C>T		intron	N/A	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.2329+918C>T		intron	N/A	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.2275+918C>T		intron	N/A	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.856 AC: 130200 AN: 152038 Hom.: 56261 Cov.: 32

Gnomad AFR AF: 0.732

Gnomad AMI AF: 0.965

Gnomad AMR AF: 0.886

Gnomad ASJ AF: 0.909

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.919

Gnomad FIN AF: 0.919

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.896

Gnomad OTH AF: 0.865

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.856 AC: 130299 AN: 152156 Hom.: 56305 Cov.: 32 AF XY: 0.860 AC XY: 63954 AN XY: 74404

African (AFR) AF: 0.732 AC: 30334 AN: 41450

American (AMR) AF: 0.886 AC: 13548 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 3154 AN: 3470

East Asian (EAS) AF: 0.993 AC: 5150 AN: 5186

South Asian (SAS) AF: 0.920 AC: 4442 AN: 4830

European-Finnish (FIN) AF: 0.919 AC: 9744 AN: 10606

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.896 AC: 60948 AN: 68012

Other (OTH) AF: 0.866 AC: 1830 AN: 2112

Alfa AF: 0.885 Hom.: 137480

Bravo AF: 0.845

Asia WGS AF: 0.949 AC: 3300 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.32
DANN	Benign	0.30
PhyloP100		-1.8
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: rs374748; hg19: chr5-127699375;