13-99985448-AGCGGCGGCG-AGCGGCGGCGGCGGCGGCG

Variant names:

• chr13-99985448-A-AGCGGCGGCG
• rs749567106
• NM_007129.5:c.1368_1376dupGGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_007129.5(ZIC2):​c.1368_1376dupGGCGGCGGC​(p.Ala457_Ala459dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000423 in 1,417,522 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A459A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: ZIC2 NM_007129.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• holoprosencephaly 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_007129.5

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007129.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC2	NM_007129.5	MANE Select	c.1368_1376dupGGCGGCGGC	p.Ala457_Ala459dup	disruptive_inframe_insertion	Exon 3 of 3	NP_009060.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC2	ENST00000376335.8	TSL:1 MANE Select	c.1368_1376dupGGCGGCGGC	p.Ala457_Ala459dup	disruptive_inframe_insertion	Exon 3 of 3	ENSP00000365514.3
	ZIC2	ENST00000468291.1	TSL:2	n.342_350dupGGCGGCGGC		non_coding_transcript_exon	Exon 3 of 3
	ZIC2	ENST00000477213.1	TSL:2	n.450_458dupGGCGGCGGC		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150892 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000443

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000237 AC: 3 AN: 1266630 Hom.: 0 Cov.: 31 AF XY: 0.00000160 AC XY: 1 AN XY: 624118

African (AFR) AF: 0.00 AC: 0 AN: 26410

American (AMR) AF: 0.00 AC: 0 AN: 23502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20732

East Asian (EAS) AF: 0.00 AC: 0 AN: 31232

South Asian (SAS) AF: 0.00 AC: 0 AN: 51340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5004

European-Non Finnish (NFE) AF: 0.00000292 AC: 3 AN: 1026474

Other (OTH) AF: 0.00 AC: 0 AN: 51774

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150892 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73636

African (AFR) AF: 0.00 AC: 0 AN: 41208

American (AMR) AF: 0.00 AC: 0 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67650

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000712 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holoprosencephaly 5 Uncertain:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1368_1376dup, results in the insertion of 3 amino acid(s) of the ZIC2 protein (p.Ala468_Ala470dup), 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. This variant has not been reported in the literature in individuals affected with ZIC2-related conditions. 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: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=70/30	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs749567106; hg19: chr13-100637702;