13-99982139-CGCGGCGGCG-CGCGGCGGCGGCG

Variant names:

• chr13-99982139-C-CGCG
• rs748109787
• NM_007129.5:c.90_92dupGGC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BP6

The NM_007129.5(ZIC2):​c.90_92dupGGC​(p.Ala31dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,330,578 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ZIC2 NM_007129.5 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.55
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_007129.5
• BP6: Variant 13-99982139-C-CGCG is Benign according to our data. Variant chr13-99982139-C-CGCG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2744216.

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.90_92dupGGC	p.Ala31dup	disruptive_inframe_insertion	Exon 1 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.90_92dupGGC	p.Ala31dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000365514.3	O95409

Frequencies

GnomAD3 genomes AF: 0.000133 AC: 20 AN: 150800 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 26028 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 125 AN: 1179680 Hom.: 0 Cov.: 30 AF XY: 0.000109 AC XY: 62 AN XY: 570104

African (AFR) AF: 0.000253 AC: 6 AN: 23754

American (AMR) AF: 0.00 AC: 0 AN: 11440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16694

East Asian (EAS) AF: 0.00 AC: 0 AN: 27410

South Asian (SAS) AF: 0.000414 AC: 18 AN: 43458

European-Finnish (FIN) AF: 0.0000366 AC: 1 AN: 27316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4052

European-Non Finnish (NFE) AF: 0.0000992 AC: 97 AN: 977722

Other (OTH) AF: 0.0000627 AC: 3 AN: 47834

GnomAD4 genome AF: 0.000133 AC: 20 AN: 150898 Hom.: 0 Cov.: 31 AF XY: 0.000122 AC XY: 9 AN XY: 73736

African (AFR) AF: 0.000266 AC: 11 AN: 41284

American (AMR) AF: 0.00 AC: 0 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10224

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

European-Non Finnish (NFE) AF: 0.0000592 AC: 4 AN: 67560

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000128

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Holoprosencephaly 5 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=68/32	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs748109787; hg19: chr13-100634393;