16-21199793-C-G

Position:

• chr16-21199793-C-G

Variant summary

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

The NM_001376232.1(ZP2):​c.1780G>C​(p.Asp594His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZP2 NM_001376232.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

Genes affected

ZP2 (HGNC:13188): (zona pellucida glycoprotein 2) The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed of three glycoproteins with various functions during fertilization and preimplantation development. The glycosylated mature peptide is one of the structural components of the zona pellucida and functions in secondary binding and penetration of acrosome-reacted spermatozoa. Female mice lacking this gene do not form a stable zona matrix and are sterile. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ZP2 (HGNC:):

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/exons	MANE	Protein	UniProt
ZP2	NM_001376232.1	c.1780G>C	p.Asp594His	missense_variant	15/19	ENST00000574091.6	NP_001363161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZP2	ENST00000574091.6	c.1780G>C	p.Asp594His	missense_variant	15/19	1	NM_001376232.1	ENSP00000458991.2
ZP2	ENST00000574002.1	c.1780G>C	p.Asp594His	missense_variant	16/20	1		ENSP00000460971.1
ENSG00000262983	ENST00000572747.1	n.340+1839C>G		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461732 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

The c.1780G>C (p.D594H) alteration is located in exon 15 (coding exon 15) of the ZP2 gene. This alteration results from a G to C substitution at nucleotide position 1780, causing the aspartic acid (D) at amino acid position 594 to be replaced by a histidine (H). 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.5	.;M
PrimateAI	Benign	0.34	T
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.98	.;D
Vest4		0.39
MutPred		0.46		.;Gain of catalytic residue at R592 (P = 0.1018);
MVP		0.94
MPC		0.39
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.47
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs1467733682; hg19: chr16-21211114;