rs1848501

Variant names:

• chr5-128436294-G-A
• rs1848501
• NM_001999.4:c.952+10187C>T

Variant summary

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

The NM_001999.4(FBN2):​c.952+10187C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 152,122 control chromosomes in the GnomAD database, including 1,066 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 0.11 (1066 hom., cov: 32)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.456
• 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: 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.952+10187C>T		intron_variant	Intron 7 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.952+10187C>T		intron_variant	Intron 7 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.952+10187C>T		intron_variant	Intron 7 of 64	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000508989.5	c.853+10187C>T		intron_variant	Intron 6 of 32	2		ENSP00000425596.1
FBN2	ENST00000508053.6	c.952+10187C>T		intron_variant	Intron 13 of 14	5		ENSP00000424571.2
FBN2	ENST00000703787.1	n.659+10187C>T		intron_variant	Intron 6 of 9

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16578 AN: 152004 Hom.: 1064 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.0947

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.0793

Gnomad EAS AF: 0.00674

Gnomad SAS AF: 0.0792

Gnomad FIN AF: 0.0973

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0945

Gnomad OTH AF: 0.100

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

GnomAD4 genome AF: 0.109 AC: 16590 AN: 152122 Hom.: 1066 Cov.: 32 AF XY: 0.108 AC XY: 8004 AN XY: 74384

African (AFR) AF: 0.171 AC: 7072 AN: 41466

American (AMR) AF: 0.0688 AC: 1051 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0793 AC: 275 AN: 3470

East Asian (EAS) AF: 0.00676 AC: 35 AN: 5180

South Asian (SAS) AF: 0.0795 AC: 383 AN: 4820

European-Finnish (FIN) AF: 0.0973 AC: 1030 AN: 10588

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0945 AC: 6423 AN: 68002

Other (OTH) AF: 0.0990 AC: 209 AN: 2112

Alfa AF: 0.0969 Hom.: 3004

Bravo AF: 0.108

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.75
PhyloP100		-0.46
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: rs1848501; hg19: chr5-127771987;