rs397515364

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_007129.5(ZIC2):​c.1318dup​(p.Leu440ProfsTer90) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

ZIC2
NM_007129.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 0.151
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_pathogenic. Variant got 7 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-99985400-G-GC is Pathogenic according to our data. Variant chr13-99985400-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 6638.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ZIC2NM_007129.5 linkuse as main transcriptc.1318dup p.Leu440ProfsTer90 frameshift_variant 3/3 ENST00000376335.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ZIC2ENST00000376335.8 linkuse as main transcriptc.1318dup p.Leu440ProfsTer90 frameshift_variant 3/31 NM_007129.5 P1
ZIC2ENST00000468291.1 linkuse as main transcriptn.292dup non_coding_transcript_exon_variant 3/32
ZIC2ENST00000477213.1 linkuse as main transcriptn.400dup non_coding_transcript_exon_variant 2/22
ZIC2ENST00000490085.5 linkuse as main transcriptn.364dup non_coding_transcript_exon_variant 3/33

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Holoprosencephaly 5 Pathogenic:2
Pathogenic, no assertion criteria providedcurationGeneReviewsAug 29, 2013- -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 1998- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs397515364; hg19: chr13-100637654; API