5-128374670-G-T

Variant names:

• chr5-128374670-G-T
• rs141291125
• NM_001999.4:c.2053C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001999.4(FBN2):​c.2053C>A​(p.Pro685Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 1.43

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 5-128374670-G-T is Benign according to our data. Variant chr5-128374670-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 458739.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.2053C>A	p.Pro685Thr	missense_variant	Exon 15 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.1900C>A	p.Pro634Thr	missense_variant	Exon 14 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.2053C>A	p.Pro685Thr	missense_variant	Exon 15 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000508989.5	c.1954C>A	p.Pro652Thr	missense_variant	Exon 14 of 33	2		ENSP00000425596.1
FBN2	ENST00000511489.1	n.274C>A		non_coding_transcript_exon_variant	Exon 3 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250934 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135576

Gnomad AFR exome AF: 0.0000615

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Benign:1

Dec 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

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	Benign	0.16
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.35	T;.;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;.;.;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.9	L;.;L;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.7	N;.;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.39	T;.;T;T
Sift4G	Benign	0.46	.;.;.;T
Polyphen		0.87	P;.;P;D
Vest4		0.58
MutPred		0.65		Loss of catalytic residue at P685 (P = 0.1564);.;Loss of catalytic residue at P685 (P = 0.1564);.;
MVP		0.75
MPC		0.54
ClinPred		0.63	D
GERP RS		4.5
Varity_R		0.14
gMVP		0.59

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: rs141291125; hg19: chr5-127710363;