chr14-74585862-T-TGGCGACTGTGGTGCGGGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4BP6BS1BS2

The NM_000428.3(LTBP2):c.804_821dupGCCCGCACCACAGTCGCC(p.Pro274_Pro275insProAlaProGlnSerPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 1,613,804 control chromosomes in the GnomAD database, including 3 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P274P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

LTBP2
NM_000428.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 1.65

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000428.3.

BP6

Variant 14-74585862-T-TGGCGACTGTGGTGCGGGC is Benign according to our data. Variant chr14-74585862-T-TGGCGACTGTGGTGCGGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 487460.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00244 (371/152192) while in subpopulation AFR AF = 0.00816 (339/41552). AF 95% confidence interval is 0.00744. There are 0 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP2	NM_000428.3 link	c.804_821dupGCCCGCACCACAGTCGCC	p.Pro274_Pro275insProAlaProGlnSerPro	disruptive_inframe_insertion	Exon 3 of 36	ENST00000261978.9	NP_000419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
LTBP2	ENST00000261978.9 link	c.804_821dupGCCCGCACCACAGTCGCC	p.Pro274_Pro275insProAlaProGlnSerPro	disruptive_inframe_insertion	Exon 3 of 36	1	NM_000428.3	ENSP00000261978.4
LTBP2	ENST00000556690.5 link	c.804_821dupGCCCGCACCACAGTCGCC	p.Pro274_Pro275insProAlaProGlnSerPro	disruptive_inframe_insertion	Exon 3 of 35	5		ENSP00000451477.1
LTBP2	ENST00000553939.5 link	n.804_821dupGCCCGCACCACAGTCGCC		non_coding_transcript_exon_variant	Exon 3 of 36	5		ENSP00000452110.1
LTBP2	ENST00000557425.1 link	n.123+26166_123+26183dupGCCCGCACCACAGTCGCC		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00244

AC:

371

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00818

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000502

AC:

125

AN:

249146

AF XY:

0.000400

show subpopulations

Gnomad AFR exome

AF:

0.00654

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000245

AC:

358

AN:

1461612

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

157

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.00864

AC:

289

AN:

33466

American (AMR)

AF:

0.000581

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111828

Other (OTH)

AF:

0.000547

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00244

AC:

371

AN:

152192

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

179

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00816

AC:

339

AN:

41552

American (AMR)

AF:

0.00163

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67972

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000435

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Weill-Marchesani syndrome 3

Uncertain:1

Aug 01, 2017

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LTBP2 NM_000428.2 exon3 p.Pro271_Ala276dup(c.804_821dup): This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame duplication of 6 amino acids at position 271 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Microspherophakia;C2751316:Glaucoma 3, primary congenital, D;C3553785:Weill-Marchesani syndrome 3

Uncertain:1

Aug 16, 2017

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LTBP2 NM_000428.2 exon 3 p. Ala276_Gly277insProGlnSerProProAla (c.821_822insGCCCGCACCACAGTCGCC): This variant has not been reported in the literature, but is present in 0.7% (180/2400) of African individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rsrs554570575). Evolutionary conservation and computational predictive tools for this variant are unavailable. This variant represents an in-frame insertion of 6 amino acids at position 276 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain._x000D_ -

Glaucoma 3, primary congenital, D;C3538951:Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma;C3553785:Weill-Marchesani syndrome 3

Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LTBP2:NM_000428:exon3, p. Ala276_Gly277insProGlnSerProProAla (c.821_822insGCCCGCACCACAGTCGCC): This variant has not been reported in the literature, but is present in 0.7% (180/2400) of African individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rsrs554570575). Evolutionary conservation and computational predictive tools for this variant are unavailable. This variant represents an in-frame insertion of 6 amino acids at position 276 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

LTBP2-related disorder

Benign:1

Feb 15, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=87/13

polymorphism

(source)

Splicing

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