14-74555568-G-T

Variant names:

• chr14-74555568-G-T
• rs2304707
• NM_000428.3:c.956C>A

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.956C>A​(p.Pro319Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0575 in 1,612,646 control chromosomes in the GnomAD database, including 3,171 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P319L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.082 (641 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2530 hom.)
• Consequence: LTBP2 NM_000428.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.664
• Publications: 22 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

ENSG00000258425 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019667745).
• BP6: Variant 14-74555568-G-T is Benign according to our data. Variant chr14-74555568-G-T is described in ClinVar as Benign. ClinVar VariationId is 256101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 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.956C>A	p.Pro319Gln	missense	Exon 4 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.956C>A	p.Pro319Gln	missense	Exon 4 of 36	ENSP00000261978.4	Q14767
	LTBP2	ENST00000945197.1		c.956C>A	p.Pro319Gln	missense	Exon 4 of 35	ENSP00000615256.1
	LTBP2	ENST00000556690.5	TSL:5	c.956C>A	p.Pro319Gln	missense	Exon 4 of 35	ENSP00000451477.1	G3V3X5

Frequencies

GnomAD3 genomes AF: 0.0816 AC: 12413 AN: 152122 Hom.: 642 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0730

Gnomad ASJ AF: 0.0923

Gnomad EAS AF: 0.0840

Gnomad SAS AF: 0.0451

Gnomad FIN AF: 0.0522

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0499

Gnomad OTH AF: 0.0856

GnomAD2 exomes AF: 0.0636 AC: 15745 AN: 247408 AF XY: 0.0613

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.0606

Gnomad ASJ exome AF: 0.0745

Gnomad EAS exome AF: 0.0907

Gnomad FIN exome AF: 0.0568

Gnomad NFE exome AF: 0.0510

Gnomad OTH exome AF: 0.0599

GnomAD4 exome AF: 0.0550 AC: 80370 AN: 1460406 Hom.: 2530 Cov.: 32 AF XY: 0.0549 AC XY: 39863 AN XY: 726452

African (AFR) AF: 0.152 AC: 5076 AN: 33464

American (AMR) AF: 0.0633 AC: 2822 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.0783 AC: 2035 AN: 25988

East Asian (EAS) AF: 0.0987 AC: 3917 AN: 39680

South Asian (SAS) AF: 0.0522 AC: 4488 AN: 85996

European-Finnish (FIN) AF: 0.0563 AC: 3007 AN: 53380

Middle Eastern (MID) AF: 0.0946 AC: 543 AN: 5742

European-Non Finnish (NFE) AF: 0.0494 AC: 54911 AN: 1111234

Other (OTH) AF: 0.0592 AC: 3571 AN: 60320

GnomAD4 genome AF: 0.0816 AC: 12417 AN: 152240 Hom.: 641 Cov.: 32 AF XY: 0.0804 AC XY: 5986 AN XY: 74434

African (AFR) AF: 0.149 AC: 6171 AN: 41540

American (AMR) AF: 0.0729 AC: 1116 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0923 AC: 320 AN: 3468

East Asian (EAS) AF: 0.0842 AC: 436 AN: 5176

South Asian (SAS) AF: 0.0452 AC: 218 AN: 4826

European-Finnish (FIN) AF: 0.0522 AC: 555 AN: 10626

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0499 AC: 3392 AN: 67984

Other (OTH) AF: 0.0847 AC: 179 AN: 2114

Alfa AF: 0.0648 Hom.: 908

Bravo AF: 0.0873

TwinsUK AF: 0.0531 AC: 197

ALSPAC AF: 0.0477 AC: 184

ESP6500AA AF: 0.160 AC: 703

ESP6500EA AF: 0.0538 AC: 463

ExAC AF: 0.0648 AC: 7863

Asia WGS AF: 0.0700 AC: 244 AN: 3478

EpiCase AF: 0.0539

EpiControl AF: 0.0556

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.77
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.66
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.20
Sift	Benign	0.28	T
Sift4G	Benign	0.40	T
Polyphen		0.88	P
Vest4		0.33
MPC		0.25
ClinPred		0.0099	T
GERP RS		-0.039
Varity_R		0.10
gMVP		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: rs2304707; hg19: chr14-75022271; COSMIC: COSV56208660;