chr13-99982346-G-A

Variant names:

• chr13-99982346-G-A
• rs886038582
• NM_007129.5:c.282G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_007129.5(ZIC2):​c.282G>A​(p.Ala94Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000761 in 1,314,422 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. A94A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: ZIC2 NM_007129.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -8.27
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP7: Synonymous conserved (PhyloP=-8.27 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC2	NM_007129.5	MANE Select	c.282G>A	p.Ala94Ala	synonymous	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.282G>A	p.Ala94Ala	synonymous	Exon 1 of 3	ENSP00000365514.3	O95409

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000133 AC: 1 AN: 75260 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: 0.0000374

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1314422 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 648202

African (AFR) AF: 0.00 AC: 0 AN: 25574

American (AMR) AF: 0.00 AC: 0 AN: 21624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22354

East Asian (EAS) AF: 0.00 AC: 0 AN: 28328

South Asian (SAS) AF: 0.00 AC: 0 AN: 70094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3898

European-Non Finnish (NFE) AF: 9.58e-7 AC: 1 AN: 1043744

Other (OTH) AF: 0.00 AC: 0 AN: 53756

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.43
DANN	Benign	0.92
PhyloP100		-8.3

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: rs886038582; hg19: chr13-100634600;