rs554570575

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_000428.3(LTBP2):c.804_821delGCCCGCACCACAGTCGCC(p.Pro269_Pro274del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,613,680 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P268P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

LTBP2
NM_000428.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U: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: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000428.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP2	NM_000428.3 link	c.804_821delGCCCGCACCACAGTCGCC	p.Pro269_Pro274del	disruptive_inframe_deletion	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_821delGCCCGCACCACAGTCGCC	p.Pro269_Pro274del	disruptive_inframe_deletion	Exon 3 of 36	1	NM_000428.3	ENSP00000261978.4
LTBP2	ENST00000556690.5 link	c.804_821delGCCCGCACCACAGTCGCC	p.Pro269_Pro274del	disruptive_inframe_deletion	Exon 3 of 35	5		ENSP00000451477.1
LTBP2	ENST00000553939.5 link	n.804_821delGCCCGCACCACAGTCGCC		non_coding_transcript_exon_variant	Exon 3 of 36	5		ENSP00000452110.1
LTBP2	ENST00000557425.1 link	n.123+26166_123+26183delGCCCGCACCACAGTCGCC		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000181

AC:

AN:

249146

AF XY:

0.000185

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000376

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000205

AC:

299

AN:

1461604

Hom.:

AF XY:

0.000206

AC XY:

150

AN XY:

727114

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000598

AC:

AN:

33466

American (AMR)

AF:

0.0000671

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:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000250

AC:

278

AN:

1111820

Other (OTH)

AF:

0.000232

AC:

AN:

60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.376

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000224

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41432

American (AMR)

AF:

0.000393

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

67980

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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:

0.000131

Hom.:

Bravo

AF:

0.000310

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Weill-Marchesani syndrome 3

Uncertain:1

May 22, 2022

3billion

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. -

not provided

Uncertain:1

Sep 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.804_821del, results in the deletion of 6 amino acid(s) of the LTBP2 protein (p.Pro271_Ala276del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs757670961, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with LTBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1365526). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

LTBP2-related disorder

Uncertain:1

Apr 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The LTBP2 c.804_821del18 variant is predicted to result in an in-frame deletion (p.Pro271_Ala276del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.034% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=182/18

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