5-128263535-G-C

Variant names:

• chr5-128263535-G-C
• rs142755118
• NM_001999.4:c.8082C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001999.4(FBN2):​c.8082C>G​(p.His2694Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H2694Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.38
• Publications: 0 publications found

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]

FBN2 Gene-Disease associations (from GenCC):

• congenital contractural arachnodactyly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11844954).
• BP6: Variant 5-128263535-G-C is Benign according to our data. Variant chr5-128263535-G-C is described in ClinVar as Benign. ClinVar VariationId is 1594061.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.8082C>G	p.His2694Gln	missense_variant	Exon 63 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.7929C>G	p.His2643Gln	missense_variant	Exon 62 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.8082C>G	p.His2694Gln	missense_variant	Exon 63 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703782.1	n.197C>G		non_coding_transcript_exon_variant	Exon 2 of 2
FBN2	ENST00000703783.1	n.*93C>G		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Benign:1

Dec 06, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.0040
DANN	Benign	0.38
DEOGEN2	Benign	0.19	T;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.70	T;.;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.7	N;.;N
PhyloP100		-4.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.75	N;.;N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T;.;T
Polyphen		0.0040	B;.;B
Vest4		0.24
MutPred		0.17		Loss of catalytic residue at H2694 (P = 0.0542);.;Loss of catalytic residue at H2694 (P = 0.0542);
MVP		0.37
MPC		0.24
ClinPred		0.047	T
GERP RS		-8.7
Varity_R		0.022
gMVP		0.30
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs142755118; hg19: chr5-127599227;