rs79445561

Positions:

• chr5-128332900-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):​c.4222+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000687 in 1,613,722 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (16 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.46

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-128332900-T-C is Benign according to our data. Variant chr5-128332900-T-C is described in ClinVar as [Benign]. Clinvar id is 137329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128332900-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0013 (198/152316) while in subpopulation EAS AF= 0.0299 (155/5176). AF 95% confidence interval is 0.0261. There are 2 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.4222+12A>G		intron_variant		ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.4069+12A>G		intron_variant			XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.4222+12A>G		intron_variant		1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152198 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0305

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00248 AC: 623 AN: 251394 Hom.: 10 AF XY: 0.00227 AC XY: 308 AN XY: 135858

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0317

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000623 AC: 911 AN: 1461406 Hom.: 16 Cov.: 31 AF XY: 0.000586 AC XY: 426 AN XY: 727014

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0190

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152316 Hom.: 2 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74476

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0299

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.00150

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.45
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs79445561; hg19: chr5-127668592;