14-74555568-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000428.3(LTBP2):c.956C>A(p.Pro319Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0575 in 1,612,646 control chromosomes in the GnomAD database, including 3,171 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P319L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.082 ( 641 hom., cov: 32)

Exomes 𝑓: 0.055 ( 2530 hom. )

Consequence

LTBP2
NM_000428.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.664

Publications

22 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019667745).

BP6

Variant 14-74555568-G-T is Benign according to our data. Variant chr14-74555568-G-T is described in ClinVar as Benign. ClinVar VariationId is 256101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP2	NM_000428.3 link	c.956C>A	p.Pro319Gln	missense_variant	Exon 4 of 36	ENST00000261978.9	NP_000419.1	Q14767
LOC124903346	XR_007064265.1 link	n.99+3155G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP2	ENST00000261978.9 link	c.956C>A	p.Pro319Gln	missense_variant	Exon 4 of 36	1	NM_000428.3	ENSP00000261978.4		Q14767

Frequencies

GnomAD3 genomes

AF:

0.0816

AC:

12413

AN:

152122

Hom.:

642

Cov.:

show subpopulations

Gnomad AFR

AF:

0.149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0730

Gnomad ASJ

AF:

0.0923

Gnomad EAS

AF:

0.0840

Gnomad SAS

AF:

0.0451

Gnomad FIN

AF:

0.0522

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0499

Gnomad OTH

AF:

0.0856

GnomAD2 exomes

AF:

0.0636

AC:

15745

AN:

247408

AF XY:

0.0613

show subpopulations

Gnomad AFR exome

AF:

0.151

Gnomad AMR exome

AF:

0.0606

Gnomad ASJ exome

AF:

0.0745

Gnomad EAS exome

AF:

0.0907

Gnomad FIN exome

AF:

0.0568

Gnomad NFE exome

AF:

0.0510

Gnomad OTH exome

AF:

0.0599

GnomAD4 exome

AF:

0.0550

AC:

80370

AN:

1460406

Hom.:

2530

Cov.:

AF XY:

0.0549

AC XY:

39863

AN XY:

726452

show subpopulations

African (AFR)

AF:

0.152

AC:

5076

AN:

33464

American (AMR)

AF:

0.0633

AC:

2822

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.0783

AC:

2035

AN:

25988

East Asian (EAS)

AF:

0.0987

AC:

3917

AN:

39680

South Asian (SAS)

AF:

0.0522

AC:

4488

AN:

85996

European-Finnish (FIN)

AF:

0.0563

AC:

3007

AN:

53380

Middle Eastern (MID)

AF:

0.0946

AC:

543

AN:

5742

European-Non Finnish (NFE)

AF:

0.0494

AC:

54911

AN:

1111234

Other (OTH)

AF:

0.0592

AC:

3571

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

4080

8160

12239

16319

20399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2178

4356

6534

8712

10890

<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:

0.0816

AC:

12417

AN:

152240

Hom.:

641

Cov.:

AF XY:

0.0804

AC XY:

5986

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.149

AC:

6171

AN:

41540

American (AMR)

AF:

0.0729

AC:

1116

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0923

AC:

320

AN:

3468

East Asian (EAS)

AF:

0.0842

AC:

436

AN:

5176

South Asian (SAS)

AF:

0.0452

AC:

218

AN:

4826

European-Finnish (FIN)

AF:

0.0522

AC:

555

AN:

10626

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0499

AC:

3392

AN:

67984

Other (OTH)

AF:

0.0847

AC:

179

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

562

1124

1687

2249

2811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<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:

0.0648

Hom.:

908

Bravo

AF:

0.0873

TwinsUK

AF:

0.0531

AC:

197

ALSPAC

AF:

0.0477

AC:

184

ESP6500AA

AF:

0.160

AC:

703

ESP6500EA

AF:

0.0538

AC:

463

ExAC

AF:

0.0648

AC:

7863

Asia WGS

AF:

0.0700

AC:

244

AN:

3478

EpiCase

AF:

0.0539

EpiControl

AF:

0.0556

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.85

T;D

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

M;.

PhyloP100

0.66

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.50

N;N

REVEL

Benign

0.20

Sift

Benign

0.28

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.88

P;.

Vest4

0.33

MPC

0.25

ClinPred

0.0099

GERP RS

-0.039

Varity_R

0.10

gMVP

0.42

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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