13-99985460-AGCGGCGGCGGCGGCTGCGGCGGCGGCG-AGCGGCGGCGGCG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A464A) has been classified as Likely benign.

• 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
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 286609.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC2	NM_007129.5	MANE Select	c.1392_1406delTGCGGCGGCGGCGGC	p.Ala465_Ala469del	disruptive_inframe_deletion	Exon 3 of 3	NP_009060.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC2	ENST00000376335.8	TSL:1 MANE Select	c.1392_1406delTGCGGCGGCGGCGGC	p.Ala465_Ala469del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000365514.3	O95409
	ZIC2	ENST00000468291.1	TSL:2	n.366_380delTGCGGCGGCGGCGGC		non_coding_transcript_exon	Exon 3 of 3
	ZIC2	ENST00000490085.5	TSL:3	n.438_452delTGCGGCGGCGGCGGC		non_coding_transcript_exon	Exon 3 of 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

GnomAD2 exomes AF: 0.000204 AC: 19 AN: 93320 AF XY: 0.000144

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 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

African (AFR) AF: 0.000198 AC: 5 AN: 25248

American (AMR) AF: 0.000493 AC: 9 AN: 18246

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 20 AN: 19342

East Asian (EAS) AF: 0.000609 AC: 18 AN: 29576

South Asian (SAS) AF: 0.000283 AC: 13 AN: 45860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27714

Middle Eastern (MID) AF: 0.000420 AC: 2 AN: 4760

European-Non Finnish (NFE) AF: 0.000247 AC: 248 AN: 1005114

Other (OTH) AF: 0.000241 AC: 12 AN: 49878

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

African (AFR) AF: 0.000170 AC: 7 AN: 41056

American (AMR) AF: 0.0000664 AC: 1 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.000872 AC: 3 AN: 3440

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5138

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4784

European-Finnish (FIN) AF: 0.000103 AC: 1 AN: 9718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000431 AC: 29 AN: 67214

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000253

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Holoprosencephaly 5 (2)
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=114/86	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs761822481; hg19: chr13-100637714;