chr14-74526070-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000428.3(LTBP2):​c.2428+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LTBP2
NM_000428.3 splice_region, intron

Scores

2
Splicing: ADA: 0.9993
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.16

Publications

1 publications found
Variant links:
Genes affected
LTBP2 (HGNC:6715): (latent transforming growth factor beta binding protein 2) The protein encoded by this gene belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multi-domain structure. This protein is the largest member of the LTBP family possessing unique regions and with most similarity to the fibrillins. It has thus been suggested that it may have multiple functions: as a member of the TGF-beta latent complex, as a structural component of microfibrils, and a role in cell adhesion. [provided by RefSeq, Jul 2008]
LTBP2 Gene-Disease associations (from GenCC):
  • glaucoma 3, primary congenital, D
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
  • microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
  • Weill-Marchesani syndrome 3
    Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • congenital glaucoma
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Weill-Marchesani syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • glaucoma secondary to spherophakia/ectopia lentis and megalocornea
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LTBP2NM_000428.3 linkc.2428+5G>T splice_region_variant, intron_variant Intron 14 of 35 ENST00000261978.9 NP_000419.1 Q14767

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LTBP2ENST00000261978.9 linkc.2428+5G>T splice_region_variant, intron_variant Intron 14 of 35 1 NM_000428.3 ENSP00000261978.4 Q14767
LTBP2ENST00000556690.5 linkc.2428+5G>T splice_region_variant, intron_variant Intron 14 of 34 5 ENSP00000451477.1 G3V3X5
LTBP2ENST00000553939.5 linkn.2428+5G>T splice_region_variant, intron_variant Intron 14 of 35 5 ENSP00000452110.1 G3V511

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1451384
Hom.:
0
Cov.:
31
AF XY:
0.00000139
AC XY:
1
AN XY:
720800
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33290
American (AMR)
AF:
0.00
AC:
0
AN:
43522
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25898
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39434
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84236
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52682
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5746
European-Non Finnish (NFE)
AF:
9.04e-7
AC:
1
AN:
1106600
Other (OTH)
AF:
0.00
AC:
0
AN:
59976
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.26
CADD
Benign
21
DANN
Benign
0.87
PhyloP100
2.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.91
SpliceAI score (max)
0.44
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.44
Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs786205624; hg19: chr14-74992773; API