rs28763923

Variant names:

• chr5-128276039-T-A
• NM_001999.4:c.7593A>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128276039-T-A
• chr5-128276039-T-C

Variant summary

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

The NM_001999.4(FBN2):​c.7593A>T​(p.Lys2531Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,416 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K2531K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense, splice_region
• Scores: Splicing: ADA: 0.9882
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.7593A>T	p.Lys2531Asn	missense_variant, splice_region_variant	Exon 59 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.7440A>T	p.Lys2480Asn	missense_variant, splice_region_variant	Exon 58 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.7593A>T	p.Lys2531Asn	missense_variant, splice_region_variant	Exon 59 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.4377A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 34 of 38

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461416 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727032

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;.
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.82	L;.;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.017	D;.;D
Polyphen		0.99	D;.;D
Vest4		0.41
MutPred		0.40		Loss of ubiquitination at K2531 (P = 0.0056);.;Loss of ubiquitination at K2531 (P = 0.0056);
MVP		0.62
MPC		0.71
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.30
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.66
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-127611731;