13-99985448-AGCGGCGGCG-AGCGGCGGCGGCG

Variant names:

• chr13-99985448-A-AGCG
• rs749567106
• NM_007129.5:c.1374_1376dupGGC

Variant summary

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

The NM_007129.5(ZIC2):​c.1374_1376dupGGC​(p.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 0.0000142 in 1,266,630 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: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC2	NM_007129.5	MANE Select	c.1374_1376dupGGC	p.Ala459dup	disruptive_inframe_insertion	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.1374_1376dupGGC	p.Ala459dup	disruptive_inframe_insertion	Exon 3 of 3	ENSP00000365514.3
	ZIC2	ENST00000468291.1	TSL:2	n.348_350dupGGC		non_coding_transcript_exon	Exon 3 of 3
	ZIC2	ENST00000477213.1	TSL:2	n.456_458dupGGC		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000142 AC: 18 AN: 1266630 Hom.: 0 Cov.: 31 AF XY: 0.0000128 AC XY: 8 AN XY: 624118

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.0000195 AC: 1 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: 0.0000166 AC: 17 AN: 1026474

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000936127), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Holoprosencephaly 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

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;