13-99985448-AGCGGCGGCG-AGCG

Variant names:

• chr13-99985448-AGCGGCG-A
• rs749567106
• NM_007129.5:c.1371_1376delGGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_007129.5(ZIC2):​c.1371_1376delGGCGGC​(p.Ala458_Ala459del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000237 in 1,266,628 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: ZIC2 NM_007129.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.94
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_007129.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC2	NM_007129.5	c.1371_1376delGGCGGC	p.Ala458_Ala459del	disruptive_inframe_deletion	Exon 3 of 3	ENST00000376335.8	NP_009060.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZIC2	ENST00000376335.8	c.1371_1376delGGCGGC	p.Ala458_Ala459del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_007129.5	ENSP00000365514.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000237 AC: 3 AN: 1266628 Hom.: 0 AF XY: 0.00000160 AC XY: 1 AN XY: 624116

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: 0.0000320 AC: 1 AN: 31232

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30160

Middle Eastern (MID) AF: 0.000200 AC: 1 AN: 5004

European-Non Finnish (NFE) AF: 9.74e-7 AC: 1 AN: 1026474

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9

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;