NM_001376232.1:c.747T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001376232.1(ZP2):​c.747T>C​(p.Pro249Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,613,452 control chromosomes in the GnomAD database, including 69,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.29 (6484 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62967 hom.)
• Consequence: ZP2 NM_001376232.1 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-21204351-A-G is Benign according to our data. Variant chr16-21204351-A-G is described in ClinVar as Benign. ClinVar VariationId is 3060177.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43529 AN: 151986 Hom.: 6465 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.307

GnomAD2 exomes AF: 0.306 AC: 76739 AN: 250884 AF XY: 0.307

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.328

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.407

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.290 AC: 424138 AN: 1461348 Hom.: 62967 Cov.: 36 AF XY: 0.292 AC XY: 212056 AN XY: 726980

African (AFR) AF: 0.233 AC: 7785 AN: 33474

American (AMR) AF: 0.328 AC: 14674 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 6746 AN: 26122

East Asian (EAS) AF: 0.419 AC: 16616 AN: 39692

South Asian (SAS) AF: 0.361 AC: 31157 AN: 86224

European-Finnish (FIN) AF: 0.304 AC: 16251 AN: 53404

Middle Eastern (MID) AF: 0.284 AC: 1635 AN: 5764

European-Non Finnish (NFE) AF: 0.280 AC: 311070 AN: 1111602

Other (OTH) AF: 0.302 AC: 18204 AN: 60378

GnomAD4 genome AF: 0.286 AC: 43575 AN: 152104 Hom.: 6484 Cov.: 32 AF XY: 0.292 AC XY: 21739 AN XY: 74344

African (AFR) AF: 0.232 AC: 9623 AN: 41502

American (AMR) AF: 0.343 AC: 5232 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 928 AN: 3470

East Asian (EAS) AF: 0.412 AC: 2129 AN: 5166

South Asian (SAS) AF: 0.375 AC: 1804 AN: 4816

European-Finnish (FIN) AF: 0.321 AC: 3394 AN: 10588

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19360 AN: 67972

Other (OTH) AF: 0.311 AC: 656 AN: 2112

Alfa AF: 0.279 Hom.: 5875

Bravo AF: 0.284

Asia WGS AF: 0.439 AC: 1523 AN: 3478

EpiCase AF: 0.286

EpiControl AF: 0.281

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ZP2-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.0
DANN	Benign	0.83
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs2075526; hg19: chr16-21215672; COSMIC: COSV54814174; COSMIC: COSV54814174;