chr14-74585862-T-TGGCGACTGTGGTGCGGGC

Variant names:

• chr14-74585862-T-TGGCGACTGTGGTGCGGGC
• rs554570575
• NM_000428.3:c.804_821dupGCCCGCACCACAGTCGCC

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_000428.3(LTBP2):​c.804_821dupGCCCGCACCACAGTCGCC​(p.Pro274_Pro275insProAlaProGlnSerPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 1,613,804 control chromosomes in the GnomAD database, including 3 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P274P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: LTBP2 NM_000428.3 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.65
• Publications: 1 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: 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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000428.3.
• BP6: Variant 14-74585862-T-TGGCGACTGTGGTGCGGGC is Benign according to our data. Variant chr14-74585862-T-TGGCGACTGTGGTGCGGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 487460.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00244 (371/152192) while in subpopulation AFR AF = 0.00816 (339/41552). AF 95% confidence interval is 0.00744. There are 0 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 Unknown,AR,AD gene

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.804_821dupGCCCGCACCACAGTCGCC	p.Pro274_Pro275insProAlaProGlnSerPro	disruptive_inframe_insertion	Exon 3 of 36	NP_000419.1	Q14767

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP2	ENST00000261978.9	TSL:1 MANE Select	c.804_821dupGCCCGCACCACAGTCGCC	p.Pro274_Pro275insProAlaProGlnSerPro	disruptive_inframe_insertion	Exon 3 of 36	ENSP00000261978.4	Q14767
	LTBP2	ENST00000945197.1		c.804_821dupGCCCGCACCACAGTCGCC	p.Pro274_Pro275insProAlaProGlnSerPro	disruptive_inframe_insertion	Exon 3 of 35	ENSP00000615256.1
	LTBP2	ENST00000556690.5	TSL:5	c.804_821dupGCCCGCACCACAGTCGCC	p.Pro274_Pro275insProAlaProGlnSerPro	disruptive_inframe_insertion	Exon 3 of 35	ENSP00000451477.1	G3V3X5

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00818

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000502 AC: 125 AN: 249146 AF XY: 0.000400

Gnomad AFR exome AF: 0.00654

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000245 AC: 358 AN: 1461612 Hom.: 3 Cov.: 32 AF XY: 0.000216 AC XY: 157 AN XY: 727120

African (AFR) AF: 0.00864 AC: 289 AN: 33466

American (AMR) AF: 0.000581 AC: 26 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111828

Other (OTH) AF: 0.000547 AC: 33 AN: 60368

GnomAD4 genome AF: 0.00244 AC: 371 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00241 AC XY: 179 AN XY: 74420

African (AFR) AF: 0.00816 AC: 339 AN: 41552

American (AMR) AF: 0.00163 AC: 25 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.0000435 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	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)
-	-	1	LTBP2-related disorder (1)
-	1	-	Microspherophakia;C2751316:Glaucoma 3, primary congenital, D;C3553785:Weill-Marchesani syndrome 3 (1)
-	1	-	Weill-Marchesani syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=87/13	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs554570575; hg19: chr14-75052565;