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
Consequence
NM_007129.5 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
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 exomes AF: 0.0000226 AC: 3AN: 132790Hom.: 0 AF XY: 0.0000128 AC XY: 1AN XY: 78048
GnomAD4 exome AF: 0.0000805 AC: 102AN: 1266626Hom.: 1 AF XY: 0.0000945 AC XY: 59AN XY: 624118
GnomAD4 genome AF: 0.0000596 AC: 9AN: 150892Hom.: 0 Cov.: 32 AF XY: 0.0000815 AC XY: 6AN XY: 73636
ClinVar
Submissions by phenotype
Holoprosencephaly 5 Uncertain:2
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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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at