rs699374

Variant names:

• chr14-74526097-A-G
• rs699374
• NM_000428.3:c.2406T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-74526097-A-G
• chr14-74526097-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000428.3(LTBP2):​c.2406T>C​(p.Thr802Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,602,476 control chromosomes in the GnomAD database, including 73,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10297 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62899 hom.)
• Consequence: LTBP2 NM_000428.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.245

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 14-74526097-A-G is Benign according to our data. Variant chr14-74526097-A-G is described in ClinVar as [Benign]. Clinvar id is 256097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74526097-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.245 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP2	NM_000428.3	c.2406T>C	p.Thr802Thr	synonymous_variant	Exon 14 of 36	ENST00000261978.9	NP_000419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP2	ENST00000261978.9	c.2406T>C	p.Thr802Thr	synonymous_variant	Exon 14 of 36	1	NM_000428.3	ENSP00000261978.4
LTBP2	ENST00000556690.5	c.2406T>C	p.Thr802Thr	synonymous_variant	Exon 14 of 35	5		ENSP00000451477.1
LTBP2	ENST00000553939.5	n.2406T>C		non_coding_transcript_exon_variant	Exon 14 of 36	5		ENSP00000452110.1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53535 AN: 151888 Hom.: 10270 Cov.: 32

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.330

GnomAD3 exomes AF: 0.305 AC: 70676 AN: 231634 Hom.: 11327 AF XY: 0.295 AC XY: 36875 AN XY: 125142

Gnomad AFR exome AF: 0.494

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.339

Gnomad SAS exome AF: 0.263

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.291 AC: 421557 AN: 1450470 Hom.: 62899 Cov.: 39 AF XY: 0.288 AC XY: 207418 AN XY: 720338

Gnomad4 AFR exome AF: 0.512

Gnomad4 AMR exome AF: 0.407

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.337

Gnomad4 SAS exome AF: 0.269

Gnomad4 FIN exome AF: 0.279

Gnomad4 NFE exome AF: 0.280

Gnomad4 OTH exome AF: 0.299

GnomAD4 genome AF: 0.353 AC: 53605 AN: 152006 Hom.: 10297 Cov.: 32 AF XY: 0.351 AC XY: 26061 AN XY: 74316

Gnomad4 AFR AF: 0.501

Gnomad4 AMR AF: 0.390

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.331

Alfa AF: 0.291 Hom.: 12434

Bravo AF: 0.372

Asia WGS AF: 0.337 AC: 1171 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 22, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 19, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Weill-Marchesani syndrome Benign:1

Jan 12, 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. -

Weill-Marchesani syndrome 3 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glaucoma 3, primary congenital, D Benign:1

Jan 12, 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. -

Microspherophakia Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.4
DANN	Benign	0.32

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

LitVar

Other links and lift over

dbSNP: rs699374; hg19: chr14-74992800; COSMIC: COSV56208711;