Genetic Variant NM_000428.3:c.2428+5G>T (chr14-74526070-C-A) – ACMG Classification: Uncertain_significance (3 pts)

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

Splicing: ADA: 0.9993

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

LTBP2 links:

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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
LTBP2	NM_000428.3 link	c.2428+5G>T		splice_region_variant, intron_variant	Intron 14 of 35	ENST00000261978.9	NP_000419.1	Q14767

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
LTBP2	ENST00000261978.9 link	c.2428+5G>T	splice_region_variant, intron_variant	Intron 14 of 35	1	NM_000428.3	ENSP00000261978.4	Q14767
LTBP2	ENST00000556690.5 link	c.2428+5G>T	splice_region_variant, intron_variant	Intron 14 of 34	5		ENSP00000451477.1	G3V3X5
LTBP2	ENST00000553939.5 link	n.2428+5G>T	splice_region_variant, intron_variant	Intron 14 of 35	5		ENSP00000452110.1	G3V511

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451384

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33290

American (AMR)

AF:

0.00

AC:

AN:

43522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25898

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.00

AC:

AN:

84236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106600

Other (OTH)

AF:

0.00

AC:

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over