13-99985448-AGCGGCGGCGGCAGCGGCGGCGGCGGCTGCGGCGGCG-AGCGGCG
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3BS2
The NM_007129.5(ZIC2):c.1377_1406delAGCGGCGGCGGCGGCTGCGGCGGCGGCGGC(p.Ala460_Ala469del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000783 in 1,417,518 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000060 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000081 ( 1 hom. )
Consequence
ZIC2
NM_007129.5 disruptive_inframe_deletion
NM_007129.5 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.22
Genes affected
ZIC2 (HGNC:12873): (Zic family member 2) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. This protein functions as a transcriptional repressor and may regulate tissue specific expression of dopamine receptor D1. Expansion of an alanine repeat in the C-terminus of the encoded protein and other mutations in this gene cause holoprosencephaly type 5. Holoprosencephaly is the most common structural anomaly of the human brain. A polyhistidine tract polymorphism in this gene may be associated with increased risk of neural tube defects. This gene is closely linked to a gene encoding zinc finger protein of the cerebellum 5, a related family member on chromosome 13. [provided by RefSeq, Jul 2016]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP3
Nonframeshift variant in repetitive region in NM_007129.5
BS2
High AC in GnomAd4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ZIC2 | NM_007129.5 | c.1377_1406delAGCGGCGGCGGCGGCTGCGGCGGCGGCGGC | p.Ala460_Ala469del | disruptive_inframe_deletion | Exon 3 of 3 | ENST00000376335.8 | NP_009060.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000596 AC: 9AN: 150892Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
9
AN:
150892
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000226 AC: 3AN: 132790Hom.: 0 AF XY: 0.0000128 AC XY: 1AN XY: 78048
GnomAD3 exomes
AF:
AC:
3
AN:
132790
Hom.:
AF XY:
AC XY:
1
AN XY:
78048
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000805 AC: 102AN: 1266626Hom.: 1 AF XY: 0.0000945 AC XY: 59AN XY: 624118
GnomAD4 exome
AF:
AC:
102
AN:
1266626
Hom.:
AF XY:
AC XY:
59
AN XY:
624118
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000596 AC: 9AN: 150892Hom.: 0 Cov.: 32 AF XY: 0.0000815 AC XY: 6AN XY: 73636
GnomAD4 genome
AF:
AC:
9
AN:
150892
Hom.:
Cov.:
32
AF XY:
AC XY:
6
AN XY:
73636
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Holoprosencephaly 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 01, 2023 | This variant has been observed in individuals with holoprosencephaly (PMID: 19177455, 21940735). This variant, c.1377_1406del, results in the deletion of 10 amino acid(s) of the ZIC2 protein (p.Ala461_Ala470del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. ClinVar contains an entry for this variant (Variation ID: 1343256). This variant disrupts a region of the ZIC2 protein in which other variant(s) (p.Ala461_465del) have been observed in individuals with ZIC2-related conditions (PMID: 19955556). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Jan 14, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at