NM_000428.3:c.220G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000428.3(LTBP2):c.220G>C(p.Glu74Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,599,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

LTBP2
NM_000428.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 2.44

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Weill-Marchesani syndrome 3
Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.104877114).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000428.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP2	NM_000428.3	MANE Select	c.220G>C	p.Glu74Gln	missense	Exon 1 of 36	NP_000419.1	Q14767

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LTBP2	ENST00000261978.9	TSL:1 MANE Select	c.220G>C	p.Glu74Gln	missense	Exon 1 of 36	ENSP00000261978.4	Q14767
LTBP2	ENST00000945197.1		c.220G>C	p.Glu74Gln	missense	Exon 1 of 35	ENSP00000615256.1
LTBP2	ENST00000556690.5	TSL:5	c.220G>C	p.Glu74Gln	missense	Exon 1 of 35	ENSP00000451477.1	G3V3X5

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000288

AC:

AN:

219006

AF XY:

0.000320

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000356

Gnomad NFE exome

AF:

0.000503

Gnomad OTH exome

AF:

0.000181

GnomAD4 exome

AF:

0.000497

AC:

719

AN:

1447366

Hom.:

Cov.:

AF XY:

0.000474

AC XY:

341

AN XY:

719932

show subpopulations

African (AFR)

AF:

0.0000899

AC:

AN:

33372

American (AMR)

AF:

0.000113

AC:

AN:

44174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.0000820

AC:

AN:

85406

European-Finnish (FIN)

AF:

0.000783

AC:

AN:

43446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000580

AC:

644

AN:

1109706

Other (OTH)

AF:

0.000433

AC:

AN:

60032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000335

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41590

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000214

Hom.:

Bravo

AF:

0.000355

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000726

AC:

ExAC

AF:

0.000342

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glaucoma 3, primary congenital, D (1)

Glaucoma 3, primary congenital, D;C3538951:Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma;C3553785:Weill-Marchesani syndrome 3 (1)

Inborn genetic diseases (1)

not provided (1)

Weill-Marchesani syndrome (1)

Weill-Marchesani syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

0.031

Eigen_PC

Benign

0.048

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.71

MutationAssessor

Benign

2.0

PhyloP100

2.4

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.46

REVEL

Benign

0.28

Sift

Benign

0.20

Sift4G

Benign

0.21

Polyphen

0.81

Vest4

0.21

MVP

0.78

MPC

1.2

ClinPred

0.11

GERP RS

3.1

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.16

gMVP

0.36

Mutation Taster

=81/19

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over