16-21204351-A-C

Variant names:

• chr16-21204351-A-C
• rs2075526
• NM_001376232.1:c.747T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001376232.1(ZP2):​c.747T>G​(p.Pro249Pro) variant causes a synonymous 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P249P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZP2 NM_001376232.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 16 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

ENSG00000262983 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZP2	NM_001376232.1	c.747T>G	p.Pro249Pro	synonymous_variant	Exon 8 of 19	ENST00000574091.6	NP_001363161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZP2	ENST00000574091.6	c.747T>G	p.Pro249Pro	synonymous_variant	Exon 8 of 19	1	NM_001376232.1	ENSP00000458991.2
ZP2	ENST00000574002.1	c.747T>G	p.Pro249Pro	synonymous_variant	Exon 9 of 20	1		ENSP00000460971.1
ZP2	ENST00000576162.5	n.774T>G		non_coding_transcript_exon_variant	Exon 8 of 9	1
ENSG00000262983	ENST00000572747.1	n.341-1394A>C		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.4
DANN	Benign	0.83
PhyloP100		1.3

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

Other links and lift over

dbSNP: rs2075526; hg19: chr16-21215672;