5-128261768-T-G

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.8332A>C(p.Lys2778Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000692 in 1,614,248 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (16 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.54

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=0.0089434385).
• BP6: Variant 5-128261768-T-G is Benign according to our data. Variant chr5-128261768-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 213371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000315 (48/152378) while in subpopulation SAS AF= 0.0089 (43/4832). AF 95% confidence interval is 0.00679. There are 1 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.8332A>C	p.Lys2778Gln	missense_variant	64/65	ENST00000262464.9
FBN2	XM_017009228.3	c.8179A>C	p.Lys2727Gln	missense_variant	63/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.8332A>C	p.Lys2778Gln	missense_variant	64/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152260 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00138 AC: 347 AN: 251176 Hom.: 6 AF XY: 0.00194 AC XY: 263 AN XY: 135736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000731 AC: 1069 AN: 1461870 Hom.: 16 Cov.: 31 AF XY: 0.00107 AC XY: 776 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000800

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152378 Hom.: 1 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74518

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00890

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000831 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00147 AC: 179

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2023	- -
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. -

FBN2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2016

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2018

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.25	T;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.61	T;.;.
MetaRNN	Benign	0.0089	T;T;T
MetaSVM	Uncertain	-0.042	T
MutationAssessor	Uncertain	2.2	M;.;M
MutationTaster	Benign	0.65	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N;.;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.028	D;.;D
Polyphen		0.46	P;.;P
Vest4		0.38
MVP		0.73
MPC		0.34
ClinPred		0.030	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.44

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: rs371715068; hg19: chr5-127597460; COSMIC: COSV105867516;