NM_000428.3:c.495-2640G>A

Variant names:

• chr14-74606345-C-T
• rs2043948
• NM_000428.3:c.495-2640G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000428.3(LTBP2):​c.495-2640G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 152,280 control chromosomes in the GnomAD database, including 1,089 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1089 hom., cov: 33)
• Consequence: LTBP2 NM_000428.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.424
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP2	NM_000428.3	c.495-2640G>A		intron_variant	Intron 1 of 35	ENST00000261978.9	NP_000419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP2	ENST00000261978.9	c.495-2640G>A		intron_variant	Intron 1 of 35	1	NM_000428.3	ENSP00000261978.4
LTBP2	ENST00000556690.5	c.495-2640G>A		intron_variant	Intron 1 of 34	5		ENSP00000451477.1
LTBP2	ENST00000553939.5	n.495-2640G>A		intron_variant	Intron 1 of 35	5		ENSP00000452110.1
LTBP2	ENST00000557425.1	n.123+5701G>A		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16678 AN: 152162 Hom.: 1084 Cov.: 33

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0616

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0777

Gnomad OTH AF: 0.116

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.110 AC: 16708 AN: 152280 Hom.: 1089 Cov.: 33 AF XY: 0.110 AC XY: 8191 AN XY: 74464

African (AFR) AF: 0.167 AC: 6940 AN: 41546

American (AMR) AF: 0.104 AC: 1594 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3472

East Asian (EAS) AF: 0.179 AC: 927 AN: 5172

South Asian (SAS) AF: 0.162 AC: 784 AN: 4828

European-Finnish (FIN) AF: 0.0616 AC: 654 AN: 10616

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0777 AC: 5287 AN: 68022

Other (OTH) AF: 0.114 AC: 241 AN: 2116

Alfa AF: 0.0908 Hom.: 1436

Bravo AF: 0.116

Asia WGS AF: 0.176 AC: 611 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.53
DANN	Benign	0.23
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2043948; hg19: chr14-75073048;