16-21199635-T-G

Position:

• chr16-21199635-T-G

Variant summary

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

The NM_001376232.1(ZP2):​c.1862A>C​(p.Asn621Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 31)
  • Exomes 𝑓: 0.018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZP2 NM_001376232.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.957

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]

ENSG00000262983 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZP2	NM_001376232.1	c.1862A>C	p.Asn621Thr	missense_variant	16/19	ENST00000574091.6	NP_001363161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZP2	ENST00000574091.6	c.1862A>C	p.Asn621Thr	missense_variant	16/19	1	NM_001376232.1	ENSP00000458991.2
ZP2	ENST00000574002.1	c.1862A>C	p.Asn621Thr	missense_variant	17/20	1		ENSP00000460971.1
ENSG00000262983	ENST00000572747.1	n.340+1681T>G		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 97 AN: 147082 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.000222

Gnomad AMI AF: 0.00112

Gnomad AMR AF: 0.000945

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00440

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000360

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0180 AC: 19962 AN: 1106286 Hom.: 0 Cov.: 33 AF XY: 0.0175 AC XY: 9715 AN XY: 556448

Gnomad4 AFR exome AF: 0.0179

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.0379

Gnomad4 EAS exome AF: 0.0478

Gnomad4 SAS exome AF: 0.00278

Gnomad4 FIN exome AF: 0.0497

Gnomad4 NFE exome AF: 0.0162

Gnomad4 OTH exome AF: 0.0291

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000645 AC: 95 AN: 147228 Hom.: 0 Cov.: 31 AF XY: 0.000612 AC XY: 44 AN XY: 71948

Gnomad4 AFR AF: 0.000246

Gnomad4 AMR AF: 0.000943

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00398

Gnomad4 SAS AF: 0.00432

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.000345

Gnomad4 OTH AF: 0.00

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

Jul 25, 2022

The c.1862A>C (p.N621T) alteration is located in exon 16 (coding exon 16) of the ZP2 gene. This alteration results from a A to C substitution at nucleotide position 1862, causing the asparagine (N) at amino acid position 621 to be replaced by a threonine (T). 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	Benign	0.23
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.18	N
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	2.0	.;M
PrimateAI	Benign	0.28	T
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.63	.;P
Vest4		0.39
MutPred		0.52		.;Loss of stability (P = 0.039);
MVP		0.87
MPC		0.22
ClinPred		0.86	D
GERP RS		4.6
Varity_R		0.18
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2093216089; hg19: chr16-21210956;