rs34600572

chr5-128278684-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):c.7296G>T(p.Gln2432His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,614,104 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (14 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0820

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.010387331).
• BP6: Variant 5-128278684-C-A is Benign according to our data. Variant chr5-128278684-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 129050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128278684-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00787 (1199/152262) while in subpopulation AFR AF= 0.0274 (1137/41540). AF 95% confidence interval is 0.026. There are 19 homozygotes in gnomad4. There are 535 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1195 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.7296G>T	p.Gln2432His	missense_variant	57/65	ENST00000262464.9
FBN2	XM_017009228.3	c.7143G>T	p.Gln2381His	missense_variant	56/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.7296G>T	p.Gln2432His	missense_variant	57/65	1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.4080G>T		non_coding_transcript_exon_variant	32/38

Frequencies

GnomAD3 genomes AF: 0.00785 AC: 1195 AN: 152144 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00223 AC: 559 AN: 251172 Hom.: 11 AF XY: 0.00174 AC XY: 236 AN XY: 135752

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000839 AC: 1226 AN: 1461842 Hom.: 14 Cov.: 31 AF XY: 0.000719 AC XY: 523 AN XY: 727226

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00787 AC: 1199 AN: 152262 Hom.: 19 Cov.: 32 AF XY: 0.00719 AC XY: 535 AN XY: 74442

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00141 Hom.: 3

Bravo AF: 0.00980

ESP6500AA AF: 0.0263 AC: 116

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00268 AC: 325

Asia WGS AF: 0.00260 AC: 9 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	FBN2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 07, 2021	- -

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Invitae	Jan 31, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Uncertain	0.55	D;.;D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.55	T;.;.
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Uncertain	0.062	D
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N;.;N
REVEL	Uncertain	0.52
Sift	Benign	0.13	T;.;T
Polyphen		0.99	D;.;D
Vest4		0.26
MutPred		0.65		Gain of ubiquitination at K2434 (P = 0.1162);.;Gain of ubiquitination at K2434 (P = 0.1162);
MVP		0.49
MPC		0.25
ClinPred		0.030	T
GERP RS		2.3
Varity_R		0.084
gMVP		0.66

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: rs34600572; hg19: chr5-127614376;