16-21211351-C-T

Variant names:

• chr16-21211351-C-T
• rs2075520
• NM_001376232.1:c.107G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001376232.1(ZP2):​c.107G>A​(p.Gly36Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G36V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZP2 NM_001376232.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.652
• Publications: 33 publications found

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 Gene-Disease associations (from GenCC):

• oocyte maturation defect 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• inherited oocyte maturation defect

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• female infertility due to zona pellucida defect

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097157985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZP2	NM_001376232.1	c.107G>A	p.Gly36Glu	missense_variant	Exon 2 of 19	ENST00000574091.6	NP_001363161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZP2	ENST00000574091.6	c.107G>A	p.Gly36Glu	missense_variant	Exon 2 of 19	1	NM_001376232.1	ENSP00000458991.2
ZP2	ENST00000574002.1	c.107G>A	p.Gly36Glu	missense_variant	Exon 3 of 20	1		ENSP00000460971.1
ZP2	ENST00000576162.5	n.134G>A		non_coding_transcript_exon_variant	Exon 2 of 9	1
ZP2	ENST00000572752.1	n.119G>A		non_coding_transcript_exon_variant	Exon 2 of 6	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 30501

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.044	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.022	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		0.65
PrimateAI	Benign	0.48	T
Sift4G	Benign	0.086	T;T
Polyphen		0.0	.;B
Vest4		0.14
MutPred		0.41		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.40
MPC		0.078
ClinPred		0.10	T
GERP RS		2.4
PromoterAI		-0.014	Neutral
Varity_R		0.062
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2075520; hg19: chr16-21222672;