NM_001999.4:c.1961G>C

Variant names:

• chr5-128376742-C-G
• rs780589159
• NM_001999.4:c.1961G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PP3_Moderate BP6_Moderate

The NM_001999.4(FBN2):​c.1961G>C​(p.Arg654Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R654H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.84
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• BP6: Variant 5-128376742-C-G is Benign according to our data. Variant chr5-128376742-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 435178.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.1961G>C	p.Arg654Pro	missense_variant	Exon 14 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.1808G>C	p.Arg603Pro	missense_variant	Exon 13 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.1961G>C	p.Arg654Pro	missense_variant	Exon 14 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000508989.5	c.1862G>C	p.Arg621Pro	missense_variant	Exon 13 of 33	2		ENSP00000425596.1
FBN2	ENST00000511489.1	n.182G>C		non_coding_transcript_exon_variant	Exon 2 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 09, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;.;.;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.6	L;.;L;.
PhyloP100		7.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.2	D;.;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0070	D;.;D;D
Sift4G	Benign	0.17	.;.;.;T
Polyphen		1.0	D;.;D;D
Vest4		0.97
MutPred		0.69		Loss of catalytic residue at R654 (P = 0.0103);.;Loss of catalytic residue at R654 (P = 0.0103);.;
MVP		0.92
MPC		1.0
ClinPred		0.82	D
GERP RS		4.6
Varity_R		0.88
gMVP		0.92
Mutation Taster		=11/89	disease causing

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: rs780589159; hg19: chr5-127712435;