13-99985460-AGCGGCGGCGGCGGCTGCGGCGGCGGCG-AGCGGCGGCGGCG

Variant names:

• chr13-99985460-AGCGGCGGCGGCGGCT-A
• rs761822481
• NM_007129.5:c.1392_1406delTGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_007129.5(ZIC2):​c.1392_1406delTGCGGCGGCGGCGGC​(p.Ala465_Ala469del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00027 in 1,375,420 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (12 hom.)
• Consequence: ZIC2 NM_007129.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 5.97

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_007129.5
• BP6: Variant 13-99985460-AGCGGCGGCGGCGGCT-A is Benign according to our data. Variant chr13-99985460-AGCGGCGGCGGCGGCT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286609.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS2: High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC2	NM_007129.5	c.1392_1406delTGCGGCGGCGGCGGC	p.Ala465_Ala469del	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.1392_1406delTGCGGCGGCGGCGGC	p.Ala465_Ala469del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_007129.5	ENSP00000365514.3

Frequencies

GnomAD3 genomes AF: 0.000294 AC: 44 AN: 149584 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.000872

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000431

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000204 AC: 19 AN: 93320 Hom.: 1 AF XY: 0.000144 AC XY: 8 AN XY: 55576

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000357

Gnomad ASJ exome AF: 0.00106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000143

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.000267 AC: 327 AN: 1225738 Hom.: 12 AF XY: 0.000263 AC XY: 158 AN XY: 600912

Gnomad4 AFR exome AF: 0.000198

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.000609

Gnomad4 SAS exome AF: 0.000283

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000247

Gnomad4 OTH exome AF: 0.000241

GnomAD4 genome AF: 0.000294 AC: 44 AN: 149682 Hom.: 0 Cov.: 32 AF XY: 0.000233 AC XY: 17 AN XY: 73030

Gnomad4 AFR AF: 0.000170

Gnomad4 AMR AF: 0.0000664

Gnomad4 ASJ AF: 0.000872

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.000103

Gnomad4 NFE AF: 0.000431

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000253

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Holoprosencephaly 5 Uncertain:2

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1392_1406del, results in the deletion of 5 amino acid(s) of the ZIC2 protein (p.Ala466_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. This variant has been observed in individuals with holoprosencephaly (PMID: 19177455, 32022405). This variant is also known as c.1366_1380del. ClinVar contains an entry for this variant (Variation ID: 286609). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Mar 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ZIC2: BP3, BS1 -

Apr 04, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

May 18, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs761822481; hg19: chr13-100637714;