Variant 13-99985448-AGCGGCGGCGGCAGCGGCGGCGGCGGCTGCGGCGGCG-AGCGGCGGCGGCAGCGGCGGCGGCGGCTGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTGCGGCGGCG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP3

The NM_007129.5(ZIC2):c.1377_1406dup(p.Ala461_Ala470dup) variant causes a inframe insertion 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 (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

ZIC2
NM_007129.5 inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.50

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]

ZIC2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-99985448-A-AGCGGCGGCGGCAGCGGCGGCGGCGGCTGCG is Pathogenic according to our data. Variant chr13-99985448-A-AGCGGCGGCGGCAGCGGCGGCGGCGGCTGCG is described in ClinVar as [Pathogenic]. Clinvar id is 468365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP3

Nonframeshift variant in repetitive region in NM_007129.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC2	NM_007129.5 linkuse as main transcript	c.1377_1406dup	p.Ala461_Ala470dup	inframe_insertion	3/3	ENST00000376335.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC2	ENST00000376335.8 linkuse as main transcript	c.1377_1406dup	p.Ala461_Ala470dup	inframe_insertion	3/3	1	NM_007129.5	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Holoprosencephaly 5

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Muenke lab, National Institutes of Health	Mar 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 03, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects ZIC2 function (PMID: 15590697). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 468365). This variant has been observed in individuals with holoprosencephaly (PMID: 9771712, 11285244, 19955556). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.1377_1406dup, results in the insertion of 10 amino acid(s) of the ZIC2 protein (p.Ala461_Ala470dup), but otherwise preserves the integrity of the reading frame. -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over