rs28763954

chr5-128408776-G-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.976C>T(p.Pro326Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00975 in 1,613,824 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (6 hom., cov: 32)
  • Exomes 𝑓: 0.010 (123 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 4.35

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=0.010052532).
• BP6: Variant 5-128408776-G-A is Benign according to our data. Variant chr5-128408776-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128408776-G-A is described in Lovd as [Benign]. Variant chr5-128408776-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00645 (982/152198) while in subpopulation NFE AF= 0.0101 (686/68004). AF 95% confidence interval is 0.00946. There are 6 homozygotes in gnomad4. There are 459 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 983 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.976C>T	p.Pro326Ser	missense_variant	8/65	ENST00000262464.9
FBN2	XM_017009228.3	c.976C>T	p.Pro326Ser	missense_variant	8/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.976C>T	p.Pro326Ser	missense_variant	8/65	1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.877C>T	p.Pro293Ser	missense_variant	7/33	2
FBN2	ENST00000508053.6	c.976C>T	p.Pro326Ser	missense_variant	14/15	5
FBN2	ENST00000703787.1	n.683C>T		non_coding_transcript_exon_variant	7/10

Frequencies

GnomAD3 genomes AF: 0.00646 AC: 983 AN: 152080 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00441

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00670 AC: 1683 AN: 251020 Hom.: 12 AF XY: 0.00671 AC XY: 910 AN XY: 135638

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00438

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00982

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.0101 AC: 14757 AN: 1461626 Hom.: 123 Cov.: 31 AF XY: 0.00992 AC XY: 7213 AN XY: 727128

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00425

Gnomad4 FIN exome AF: 0.00275

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.00645 AC: 982 AN: 152198 Hom.: 6 Cov.: 32 AF XY: 0.00617 AC XY: 459 AN XY: 74402

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00974 Hom.: 13

Bravo AF: 0.00674

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.00656 AC: 796

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0118

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital contractural arachnodactyly Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 25, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 27, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	This variant is associated with the following publications: (PMID: 18767143, 20981092, 27884173, 27007659, 31316167) -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2017	Variant summary: The FBN2 c.976C>T (p.Pro326Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC, in 796/121328 control chromosomes (6 homozygotes) at a frequency of 0.0065607, which is approximately 140 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000469), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	FBN2: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 12, 2023	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 02, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 25, 2015	- -

Connective tissue disorder Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jan 22, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2014

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;D;D
Eigen	Benign	0.012
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;.;.;T
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Uncertain	0.0025	D
MutationAssessor	Benign	1.4	L;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.2	D;.;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.10	T;.;T;T
Polyphen		0.074	B;.;B;B
Vest4		0.21
MVP		0.61
MPC		0.35
ClinPred		0.031	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.52

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: rs28763954; hg19: chr5-127744469;