13-99982277-G-C

Variant names:

• chr13-99982277-G-C
• rs189469383
• NM_007129.5:c.213G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_007129.5(ZIC2):​c.213G>C​(p.Pro71Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,343,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P71P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ZIC2 NM_007129.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.43
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=-3.43 with no splicing effect.

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.213G>C	p.Pro71Pro	synonymous	Exon 1 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.213G>C	p.Pro71Pro	synonymous	Exon 1 of 3	ENSP00000365514.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000126 AC: 17 AN: 1343930 Hom.: 0 Cov.: 31 AF XY: 0.00000753 AC XY: 5 AN XY: 663982

African (AFR) AF: 0.00 AC: 0 AN: 27334

American (AMR) AF: 0.00 AC: 0 AN: 30446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23550

East Asian (EAS) AF: 0.00 AC: 0 AN: 29914

South Asian (SAS) AF: 0.00 AC: 0 AN: 74638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4460

European-Non Finnish (NFE) AF: 0.0000151 AC: 16 AN: 1059102

Other (OTH) AF: 0.0000181 AC: 1 AN: 55358

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.67
PhyloP100		-3.4
PromoterAI		-0.00060	Neutral

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: rs189469383; hg19: chr13-100634531;