chr14-74552299-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000428.3(LTBP2):c.1287G>A(p.Leu429Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.056 in 1,613,186 control chromosomes in the GnomAD database, including 2,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 339 hom., cov: 32)

Exomes 𝑓: 0.055 ( 2403 hom. )

Consequence

LTBP2
NM_000428.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.751

Publications

15 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:

ENSG00000258425 (HGNC:):

ENSG00000258425 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 14-74552299-C-T is Benign according to our data. Variant chr14-74552299-C-T is described in ClinVar as Benign. ClinVar VariationId is 256096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP2	NM_000428.3 link	c.1287G>A	p.Leu429Leu	synonymous_variant	Exon 6 of 36	ENST00000261978.9	NP_000419.1	Q14767
LOC124903346	XR_007064265.1 link	n.-16C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP2	ENST00000261978.9 link	c.1287G>A	p.Leu429Leu	synonymous_variant	Exon 6 of 36	1	NM_000428.3	ENSP00000261978.4		Q14767

Frequencies

GnomAD3 genomes

AF:

0.0638

AC:

9704

AN:

152168

Hom.:

340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0837

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0677

Gnomad ASJ

AF:

0.0937

Gnomad EAS

AF:

0.0801

Gnomad SAS

AF:

0.0447

Gnomad FIN

AF:

0.0520

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0516

Gnomad OTH

AF:

0.0702

GnomAD2 exomes

AF:

0.0597

AC:

14854

AN:

249004

AF XY:

0.0587

show subpopulations

Gnomad AFR exome

AF:

0.0874

Gnomad AMR exome

AF:

0.0584

Gnomad ASJ exome

AF:

0.0753

Gnomad EAS exome

AF:

0.0862

Gnomad FIN exome

AF:

0.0566

Gnomad NFE exome

AF:

0.0527

Gnomad OTH exome

AF:

0.0616

GnomAD4 exome

AF:

0.0552

AC:

80634

AN:

1460900

Hom.:

2403

Cov.:

AF XY:

0.0553

AC XY:

40204

AN XY:

726762

show subpopulations

African (AFR)

AF:

0.0847

AC:

2837

AN:

33480

American (AMR)

AF:

0.0608

AC:

2718

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0796

AC:

2081

AN:

26136

East Asian (EAS)

AF:

0.0963

AC:

3822

AN:

39700

South Asian (SAS)

AF:

0.0528

AC:

4554

AN:

86258

European-Finnish (FIN)

AF:

0.0565

AC:

2968

AN:

52536

Middle Eastern (MID)

AF:

0.0955

AC:

551

AN:

5768

European-Non Finnish (NFE)

AF:

0.0519

AC:

57667

AN:

1111928

Other (OTH)

AF:

0.0569

AC:

3436

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

4871

9743

14614

19486

24357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2244

4488

6732

8976

11220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0637

AC:

9702

AN:

152286

Hom.:

339

Cov.:

AF XY:

0.0636

AC XY:

4734

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0835

AC:

3471

AN:

41564

American (AMR)

AF:

0.0676

AC:

1034

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0937

AC:

325

AN:

3470

East Asian (EAS)

AF:

0.0803

AC:

415

AN:

5170

South Asian (SAS)

AF:

0.0448

AC:

216

AN:

4826

European-Finnish (FIN)

AF:

0.0520

AC:

552

AN:

10620

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0516

AC:

3511

AN:

68012

Other (OTH)

AF:

0.0695

AC:

147

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

455

909

1364

1818

2273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0591

Hom.:

161

Bravo

AF:

0.0671

Asia WGS

AF:

0.0690

AC:

239

AN:

3478

EpiCase

AF:

0.0556

EpiControl

AF:

0.0573

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Weill-Marchesani syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Glaucoma 3, primary congenital, D

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.75

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over