14-74863188-G-A

Variant names:

• chr14-74863188-G-A
• rs192730740
• NM_001243007.2:c.647C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001243007.2(PROX2):​c.647C>T​(p.Pro216Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000471 in 1,614,042 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: PROX2 NM_001243007.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048573256).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243007.2. 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
	PROX2	NM_001243007.2	MANE Select	c.647C>T	p.Pro216Leu	missense	Exon 3 of 6	NP_001229936.1	G3V3G0
	PROX2	NM_001384314.1		c.647C>T	p.Pro216Leu	missense	Exon 4 of 7	NP_001371243.1	G3V3G0
	PROX2	NM_001080408.3		c.647C>T	p.Pro216Leu	missense	Exon 3 of 5	NP_001073877.2	Q3B8N5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROX2	ENST00000556489.4	TSL:1 MANE Select	c.647C>T	p.Pro216Leu	missense	Exon 3 of 6	ENSP00000451223.2	G3V3G0
	PROX2	ENST00000673765.1		c.647C>T	p.Pro216Leu	missense	Exon 3 of 5	ENSP00000501015.1	Q3B8N5-2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000281 AC: 70 AN: 249084 AF XY: 0.000281

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000567

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000494 AC: 722 AN: 1461708 Hom.: 0 Cov.: 32 AF XY: 0.000487 AC XY: 354 AN XY: 727138

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000628 AC: 698 AN: 1111870

Other (OTH) AF: 0.000232 AC: 14 AN: 60374

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74498

African (AFR) AF: 0.0000722 AC: 3 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000469 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.000339 AC: 41

EpiCase AF: 0.000164

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.065
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.32	T
Polyphen		0.25	B
Vest4		0.23
MVP		0.28
MPC		0.32
ClinPred		0.15	T
GERP RS		4.9
gMVP		0.21
Mutation Taster		=90/10	polymorphism

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: rs192730740; hg19: chr14-75329891; COSMIC: COSV105832003;