14-74863267-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001243007.2(PROX2):​c.568G>A​(p.Gly190Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PROX2
NM_001243007.2 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.363
Variant links:
Genes affected
PROX2 (HGNC:26715): (prospero homeobox 2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.014933407).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PROX2NM_001243007.2 linkuse as main transcriptc.568G>A p.Gly190Ser missense_variant 3/6 ENST00000556489.4 NP_001229936.1 Q3B8N5G3V3G0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PROX2ENST00000556489.4 linkuse as main transcriptc.568G>A p.Gly190Ser missense_variant 3/61 NM_001243007.2 ENSP00000451223.2 G3V3G0
PROX2ENST00000673765.1 linkuse as main transcriptc.568G>A p.Gly190Ser missense_variant 3/5 ENSP00000501015.1 Q3B8N5-2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000766
AC:
19
AN:
248132
Hom.:
0
AF XY:
0.000111
AC XY:
15
AN XY:
134784
show subpopulations
Gnomad AFR exome
AF:
0.0000654
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000556
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000445
AC:
65
AN:
1461512
Hom.:
0
Cov.:
32
AF XY:
0.0000660
AC XY:
48
AN XY:
727022
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000719
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152344
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000827
AC:
10

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 09, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.64
T
BayesDel_noAF
Benign
-0.80
CADD
Benign
0.61
DANN
Benign
0.32
DEOGEN2
Benign
0.0017
.;T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.013
N
LIST_S2
Benign
0.60
T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.015
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-2.6
N;.
PrimateAI
Benign
0.21
T
PROVEAN
Benign
1.2
N;N
REVEL
Benign
0.014
Sift
Benign
1.0
T;T
Sift4G
Benign
0.85
T;T
Polyphen
0.0
B;B
Vest4
0.086
MVP
0.030
MPC
0.047
ClinPred
0.042
T
GERP RS
-0.68
gMVP
0.076

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs541503864; hg19: chr14-75329970; API