rs2159905

Variant names:

• chr14-74876324-A-G
• rs2159905
• NM_001243007.2:c.-739T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001243007.2(PROX2):​c.-739T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,158 control chromosomes in the GnomAD database, including 2,755 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2755 hom., cov: 32)
• Consequence: PROX2 NM_001243007.2 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.710
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROX2	NM_001243007.2	c.-739T>C		upstream_gene_variant		ENST00000556489.4	NP_001229936.1
PROX2	NM_001384314.1	c.-816T>C		upstream_gene_variant			NP_001371243.1
PROX2	NM_001080408.3	c.-739T>C		upstream_gene_variant			NP_001073877.2
PROX2	NR_169190.1	n.-179T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROX2	ENST00000556489.4	c.-739T>C		upstream_gene_variant		1	NM_001243007.2	ENSP00000451223.2
PROX2	ENST00000673765.1	c.-739T>C		upstream_gene_variant				ENSP00000501015.1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27652 AN: 152038 Hom.: 2758 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.161

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.182 AC: 27661 AN: 152158 Hom.: 2755 Cov.: 32 AF XY: 0.188 AC XY: 14012 AN XY: 74410

African (AFR) AF: 0.236 AC: 9782 AN: 41496

American (AMR) AF: 0.185 AC: 2825 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 332 AN: 3468

East Asian (EAS) AF: 0.207 AC: 1072 AN: 5184

South Asian (SAS) AF: 0.294 AC: 1421 AN: 4826

European-Finnish (FIN) AF: 0.228 AC: 2420 AN: 10592

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9281 AN: 67982

Other (OTH) AF: 0.159 AC: 336 AN: 2112

Alfa AF: 0.152 Hom.: 4761

Bravo AF: 0.178

Asia WGS AF: 0.244 AC: 850 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.73
DANN	Benign	0.64
PhyloP100		-0.71
PromoterAI		0.034	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2159905; hg19: chr14-75343027;