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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.22
Variant links:
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]

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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
ZIC2NM_007129.5 linkc.1377_1406delAGCGGCGGCGGCGGCTGCGGCGGCGGCGGC p.Ala460_Ala469del disruptive_inframe_deletion Exon 3 of 3 ENST00000376335.8 NP_009060.2 O95409A0A024RDY6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZIC2ENST00000376335.8 linkc.1377_1406delAGCGGCGGCGGCGGCTGCGGCGGCGGCGGC p.Ala460_Ala469del disruptive_inframe_deletion Exon 3 of 3 1 NM_007129.5 ENSP00000365514.3 O95409

Frequencies

GnomAD3 genomes
AF:
0.0000596
AC:
9
AN:
150892
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000971
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000739
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000226
AC:
3
AN:
132790
Hom.:
0
AF XY:
0.0000128
AC XY:
1
AN XY:
78048
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000433
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000805
AC:
102
AN:
1266626
Hom.:
1
AF XY:
0.0000945
AC XY:
59
AN XY:
624118
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000390
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000925
Gnomad4 OTH exome
AF:
0.0000966
GnomAD4 genome
AF:
0.0000596
AC:
9
AN:
150892
Hom.:
0
Cov.:
32
AF XY:
0.0000815
AC XY:
6
AN XY:
73636
show subpopulations
Gnomad4 AFR
AF:
0.0000971
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000739
Gnomad4 OTH
AF:
0.00

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 01, 2023This 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 submitterclinical testingInstitute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital BonnJan 14, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs756225250; hg19: chr13-100637702; API