rs371491169

chr5-128537511-C-Achr5-128537511-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001999.4(FBN2):c.93G>T(p.Gln31His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 1,577,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.601

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.057896286).
• BP6: Variant 5-128537511-C-A is Benign according to our data. Variant chr5-128537511-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 510894.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000119 (17/1425126) while in subpopulation AFR AF= 0.000427 (14/32796). AF 95% confidence interval is 0.000257. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.93G>T	p.Gln31His	missense_variant	1/65	ENST00000262464.9
FBN2	XM_017009228.3	c.93G>T	p.Gln31His	missense_variant	1/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.93G>T	p.Gln31His	missense_variant	1/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152088 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000490 AC: 9 AN: 183640 Hom.: 0 AF XY: 0.0000700 AC XY: 7 AN XY: 100030

Gnomad AFR exome AF: 0.000751

Gnomad AMR exome AF: 0.0000352

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 17 AN: 1425126 Hom.: 0 Cov.: 32 AF XY: 0.0000142 AC XY: 10 AN XY: 706150

Gnomad4 AFR exome AF: 0.000427

Gnomad4 AMR exome AF: 0.0000499

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: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74416

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000125

ESP6500AA AF: 0.000467 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000424 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FBN2 p.Gln31His variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs371491169) and in ClinVar (classified as likely benign by GeneDx.) The variant was also identified in control databases in 10 of 214970 chromosomes at a frequency of 0.000047 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 9 of 19356 chromosomes (freq: 0.000465) and Latino in 1 of 29282 chromosomes (freq: 0.000034), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gln31 residue is not conserved in mammals and all computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2018	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2 related disorders (Collod-Beroud et al., 2003; Frederic et al., 2009). -

Congenital contractural arachnodactyly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;T;T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.83	T;.;.;T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.058	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.81	L;.;L;.;.
MutationTaster	Benign	0.82	N;N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.72	N;.;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.11	T;.;T;T;T
Polyphen		0.0	B;.;B;B;B
Vest4		0.23
MutPred		0.18		Gain of glycosylation at T26 (P = 0.2372);Gain of glycosylation at T26 (P = 0.2372);Gain of glycosylation at T26 (P = 0.2372);Gain of glycosylation at T26 (P = 0.2372);Gain of glycosylation at T26 (P = 0.2372);
MVP		0.52
MPC		0.22
ClinPred		0.029	T
GERP RS		3.0
Varity_R		0.061
gMVP		0.57

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: rs371491169; hg19: chr5-127873204;