rs28763945

chr5-128345408-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.3166G>T(p.Ala1056Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00143 in 1,614,162 control chromosomes in the GnomAD database, including 26 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 0.0072 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (15 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.15

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=0.009017587).
• BP6: Variant 5-128345408-C-A is Benign according to our data. Variant chr5-128345408-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 137324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128345408-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00723 (1101/152272) while in subpopulation AFR AF= 0.0248 (1031/41572). AF 95% confidence interval is 0.0235. There are 11 homozygotes in gnomad4. There are 498 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1098 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.3166G>T	p.Ala1056Ser	missense_variant	24/65	ENST00000262464.9
FBN2	XM_017009228.3	c.3013G>T	p.Ala1005Ser	missense_variant	23/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.3166G>T	p.Ala1056Ser	missense_variant	24/65	1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.3067G>T	p.Ala1023Ser	missense_variant	23/33	2

Frequencies

GnomAD3 genomes AF: 0.00722 AC: 1098 AN: 152154 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00191 AC: 481 AN: 251420 Hom.: 4 AF XY: 0.00139 AC XY: 189 AN XY: 135902

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000830 AC: 1213 AN: 1461890 Hom.: 15 Cov.: 32 AF XY: 0.000752 AC XY: 547 AN XY: 727246

Gnomad4 AFR exome AF: 0.0273

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00723 AC: 1101 AN: 152272 Hom.: 11 Cov.: 32 AF XY: 0.00669 AC XY: 498 AN XY: 74436

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00178 Hom.: 4

Bravo AF: 0.00830

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00228 AC: 277

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2013	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2023	- -

not provided Benign:2

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 16, 2023	- -

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 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

Nov 01, 2021

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.;T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.59	T;.;.;T
MetaRNN	Benign	0.0090	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.55	N;.;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.10	N;.;N;N
REVEL	Benign	0.26
Sift	Benign	0.31	T;.;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.12
MVP		0.35
MPC		0.21
ClinPred		0.0023	T
GERP RS		3.5
Varity_R		0.037
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: rs28763945; hg19: chr5-127681100;