rs78258030

Variant names:

• chr14-74521898-G-A
• rs78258030
• NM_000428.3:c.2788+13C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000428.3(LTBP2):​c.2788+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,613,784 control chromosomes in the GnomAD database, including 823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (184 hom., cov: 33)
  • Exomes 𝑓: 0.019 (639 hom.)
• Consequence: LTBP2 NM_000428.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.69
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 14-74521898-G-A is Benign according to our data. Variant chr14-74521898-G-A is described in ClinVar as Benign. ClinVar VariationId is 256098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0815 is higher than 0.05.

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.2788+13C>T		intron	N/A	NP_000419.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP2	ENST00000261978.9	TSL:1 MANE Select	c.2788+13C>T		intron	N/A	ENSP00000261978.4
	LTBP2	ENST00000945197.1		c.2686+13C>T		intron	N/A	ENSP00000615256.1
	LTBP2	ENST00000556690.5	TSL:5	c.2788+13C>T		intron	N/A	ENSP00000451477.1

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5323 AN: 152194 Hom.: 185 Cov.: 33

Gnomad AFR AF: 0.0841

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0821

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0246 AC: 6182 AN: 251064 AF XY: 0.0269

Gnomad AFR exome AF: 0.0866

Gnomad AMR exome AF: 0.00995

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00783

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0187 AC: 27365 AN: 1461474 Hom.: 639 Cov.: 32 AF XY: 0.0205 AC XY: 14902 AN XY: 727054

African (AFR) AF: 0.0858 AC: 2872 AN: 33476

American (AMR) AF: 0.0107 AC: 479 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26134

East Asian (EAS) AF: 0.000756 AC: 30 AN: 39692

South Asian (SAS) AF: 0.0823 AC: 7102 AN: 86244

European-Finnish (FIN) AF: 0.00813 AC: 433 AN: 53278

Middle Eastern (MID) AF: 0.0216 AC: 123 AN: 5696

European-Non Finnish (NFE) AF: 0.0135 AC: 15058 AN: 1111876

Other (OTH) AF: 0.0198 AC: 1197 AN: 60370

GnomAD4 genome AF: 0.0349 AC: 5316 AN: 152310 Hom.: 184 Cov.: 33 AF XY: 0.0348 AC XY: 2591 AN XY: 74466

African (AFR) AF: 0.0838 AC: 3484 AN: 41562

American (AMR) AF: 0.0195 AC: 299 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5182

South Asian (SAS) AF: 0.0815 AC: 393 AN: 4820

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10622

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0141 AC: 959 AN: 68036

Other (OTH) AF: 0.0265 AC: 56 AN: 2112

Alfa AF: 0.0262 Hom.: 24

Bravo AF: 0.0354

Asia WGS AF: 0.0460 AC: 161 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Glaucoma 3, primary congenital, D (1)
-	-	1	Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.0050
DANN	Benign	0.34
PhyloP100		-2.7
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: rs78258030; hg19: chr14-74988601;