chr5-128374657-G-T

Variant names:

• chr5-128374657-G-T
• rs781745158
• NM_001999.4:c.2066C>A

Variant summary

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

The NM_001999.4(FBN2):​c.2066C>A​(p.Ala689Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.95

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.2066C>A	p.Ala689Asp	missense_variant	Exon 15 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.1913C>A	p.Ala638Asp	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.2066C>A	p.Ala689Asp	missense_variant	Exon 15 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000508989.5	c.1967C>A	p.Ala656Asp	missense_variant	Exon 14 of 33	2		ENSP00000425596.1
FBN2	ENST00000511489.1	n.287C>A		non_coding_transcript_exon_variant	Exon 3 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250944 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135598

Gnomad AFR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461676 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727142

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;D;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T;.;.;T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	-0.036	T
MutationAssessor	Benign	1.2	L;.;L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.9	D;.;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.021	D;.;D;D
Sift4G	Benign	0.14	.;.;.;T
Polyphen		0.93	P;.;P;B
Vest4		0.88
MutPred		0.58		Gain of disorder (P = 0.0172);.;Gain of disorder (P = 0.0172);.;
MVP		0.83
MPC		0.44
ClinPred		0.88	D
GERP RS		4.5
Varity_R		0.46
gMVP		0.68

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: rs781745158; hg19: chr5-127710350;