dbSNP rs200874751: PROX2:p.Pro591Ser (chr14-74855140-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_001243007.2(PROX2):c.1771C>T(p.Pro591Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,405,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P591T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PROX2
NM_001243007.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.18

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]

PROX2 links:

YLPM1 (HGNC:17798): (YLP motif containing 1) Enables RNA binding activity. Predicted to be involved in regulation of telomere maintenance. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

YLPM1 links:

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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=0.040171504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROX2	NM_001243007.2 link	c.1771C>T	p.Pro591Ser	missense_variant	Exon 6 of 6	ENST00000556489.4	NP_001229936.1	Q3B8N5G3V3G0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PROX2	ENST00000556489.4 link	c.1771C>T	p.Pro591Ser	missense_variant	Exon 6 of 6	1	NM_001243007.2	ENSP00000451223.2	G3V3G0
PROX2	ENST00000673765.1 link	c.1090C>T	p.Pro364Ser	missense_variant	Exon 5 of 5			ENSP00000501015.1	Q3B8N5-2
YLPM1	ENST00000554107.2 link	c.205-77G>A		intron_variant	Intron 3 of 3	3		ENSP00000476212.1	U3KQT9
YLPM1	ENST00000553381.1 link	n.238-77G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1405292

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

691784

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000186

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.015

.;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.040

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.076

Sift

Benign

0.59

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.047

B;B

Vest4

0.043

MutPred

0.12

.;Gain of phosphorylation at P591 (P = 0.0069);

MVP

0.18

MPC

0.052

ClinPred

0.089

GERP RS

2.4

gMVP

0.31

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over