rs765437414

Positions:

• chr5-128344438-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP2 BP6 BS2

The NM_001999.4(FBN2):​c.3290A>C​(p.Lys1097Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1097R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.02

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_001999.4
• PP2: Missense variant where missense usually causes diseases, FBN2
• BP6: Variant 5-128344438-T-G is Benign according to our data. Variant chr5-128344438-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458756.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.3290A>C	p.Lys1097Thr	missense_variant	25/65	ENST00000262464.9
FBN2	XM_017009228.3	c.3137A>C	p.Lys1046Thr	missense_variant	24/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.3290A>C	p.Lys1097Thr	missense_variant	25/65	1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.3191A>C	p.Lys1064Thr	missense_variant	24/33	2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251422 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000411 AC: 60 AN: 1461552 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 14, 2020

Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Frederic et al., 2009); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 458756; Landrum et al., 2016) -

Congenital contractural arachnodactyly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	D;.;D;D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;.;.;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	-0.71	N;.;N;.
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D;.;D;D
REVEL	Uncertain	0.58
Sift	Benign	0.28	T;.;T;T
Polyphen		0.50	P;.;P;P
Vest4		0.63
MutPred		0.67		Loss of methylation at K1097 (P = 2e-04);.;Loss of methylation at K1097 (P = 2e-04);.;
MVP		0.85
MPC		0.68
ClinPred		0.75	D
GERP RS		4.3
Varity_R		0.15
gMVP		0.60

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: rs765437414; hg19: chr5-127680130;