chr13-99986138-G-A

Variant names:

• chr13-99986138-G-A
• rs13542
• NM_007129.5:c.*456G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007129.5(ZIC2):​c.*456G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 441,306 control chromosomes in the GnomAD database, including 16,691 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (7662 hom., cov: 32)
  • Exomes 𝑓: 0.24 (9029 hom.)
• Consequence: ZIC2 NM_007129.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• Publications: 14 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC2	NM_007129.5	MANE Select	c.*456G>A		3_prime_UTR	Exon 3 of 3	NP_009060.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC2	ENST00000376335.8	TSL:1 MANE Select	c.*456G>A		3_prime_UTR	Exon 3 of 3	ENSP00000365514.3
	ZIC2	ENST00000481565.1	TSL:2	n.*234G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45560 AN: 151894 Hom.: 7650 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.321

GnomAD4 exome AF: 0.242 AC: 70089 AN: 289294 Hom.: 9029 Cov.: 0 AF XY: 0.239 AC XY: 39506 AN XY: 165210

African (AFR) AF: 0.470 AC: 3760 AN: 8006

American (AMR) AF: 0.263 AC: 6298 AN: 23990

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 3179 AN: 10208

East Asian (EAS) AF: 0.282 AC: 2547 AN: 9016

South Asian (SAS) AF: 0.222 AC: 12375 AN: 55830

European-Finnish (FIN) AF: 0.181 AC: 2201 AN: 12132

Middle Eastern (MID) AF: 0.319 AC: 869 AN: 2722

European-Non Finnish (NFE) AF: 0.230 AC: 35310 AN: 153798

Other (OTH) AF: 0.261 AC: 3550 AN: 13592

GnomAD4 genome AF: 0.300 AC: 45601 AN: 152012 Hom.: 7662 Cov.: 32 AF XY: 0.297 AC XY: 22066 AN XY: 74308

African (AFR) AF: 0.461 AC: 19101 AN: 41438

American (AMR) AF: 0.292 AC: 4471 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1092 AN: 3472

East Asian (EAS) AF: 0.283 AC: 1465 AN: 5180

South Asian (SAS) AF: 0.218 AC: 1049 AN: 4806

European-Finnish (FIN) AF: 0.180 AC: 1898 AN: 10548

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15621 AN: 67966

Other (OTH) AF: 0.323 AC: 681 AN: 2110

Alfa AF: 0.261 Hom.: 15369

Bravo AF: 0.314

Asia WGS AF: 0.296 AC: 1028 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.78
DANN	Benign	0.72
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs13542; hg19: chr13-100638392;