14-74585862-TGGCGACTGTGGTGCGGGC-TGGCGACTGTGGTGCGGGCGGCGACTGTGGTGCGGGC

Position:

chr14-74585862-TGGCGACTGTGGTGCGGGC-TGGCGACTGTGGTGCGGGCGGCGACTGTGGTGCGGGC

Variant summary

Our verdict is Benign. Variant got -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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 487460.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1, Benign=1}.

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP2	NM_000428.3 link	c.804_821dupGCCCGCACCACAGTCGCC	p.Pro274_Pro275insProAlaProGlnSerPro	disruptive_inframe_insertion	3/36	ENST00000261978.9	NP_000419.1	Q14767

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LTBP2	ENST00000261978.9 link	c.804_821dupGCCCGCACCACAGTCGCC	p.Pro274_Pro275insProAlaProGlnSerPro	disruptive_inframe_insertion	3/36	1	NM_000428.3	ENSP00000261978.4	Q14767
LTBP2	ENST00000556690.5 link	c.804_821dupGCCCGCACCACAGTCGCC	p.Pro274_Pro275insProAlaProGlnSerPro	disruptive_inframe_insertion	3/35	5		ENSP00000451477.1	G3V3X5
LTBP2	ENST00000553939.5 link	n.804_821dupGCCCGCACCACAGTCGCC		non_coding_transcript_exon_variant	3/36	5		ENSP00000452110.1	G3V511
LTBP2	ENST00000557425.1 link	n.123+26166_123+26183dupGCCCGCACCACAGTCGCC		intron_variant		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

GnomAD3 exomes

AF:

0.000502

AC:

125

AN:

249146

Hom.:

AF XY:

0.000400

AC XY:

AN XY:

134872

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 SAS 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

Gnomad4 AFR exome

AF:

0.00864

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.000547

GnomAD4 genome

AF:

0.00244

AC:

371

AN:

152192

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

179

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00816

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00284

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2020	- -

Weill-Marchesani syndrome 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 01, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 16, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2021

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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over