14-74856990-G-C

Variant names:

• chr14-74856990-G-C
• rs1430665745
• NM_001243007.2:c.1419C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001243007.2(PROX2):​c.1419C>G​(p.Asn473Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,494 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (1 hom.)
• Consequence: PROX2 NM_001243007.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROX2	NM_001243007.2	c.1419C>G	p.Asn473Lys	missense_variant	Exon 5 of 6	ENST00000556489.4	NP_001229936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROX2	ENST00000556489.4	c.1419C>G	p.Asn473Lys	missense_variant	Exon 5 of 6	1	NM_001243007.2	ENSP00000451223.2
PROX2	ENST00000673765.1	c.738C>G	p.Asn246Lys	missense_variant	Exon 4 of 5			ENSP00000501015.1
YLPM1	ENST00000554107.2	c.*1648G>C		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000476212.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461494 Hom.: 1 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727028

Gnomad4 AFR exome AF: 0.0000597

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: 0.00

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.738C>G (p.N246K) alteration is located in exon 2 (coding exon 2) of the PROX2 gene. This alteration results from a C to G substitution at nucleotide position 738, causing the asparagine (N) at amino acid position 246 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.32	T
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.98	D;D
Vest4		0.63
MutPred		0.58		.;Gain of methylation at N473 (P = 0.0026);
MVP		0.37
MPC		0.23
ClinPred		0.99	D
GERP RS		1.2
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1430665745; hg19: chr14-75323693;