13-99982147-C-A

Variant names:

• chr13-99982147-C-A
• rs745788400
• NM_007129.5:c.83C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007129.5(ZIC2):​c.83C>A​(p.Ala28Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,338,722 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: ZIC2 NM_007129.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC2	NM_007129.5	c.83C>A	p.Ala28Glu	missense_variant	Exon 1 of 3	ENST00000376335.8	NP_009060.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZIC2	ENST00000376335.8	c.83C>A	p.Ala28Glu	missense_variant	Exon 1 of 3	1	NM_007129.5	ENSP00000365514.3

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.42e-7 AC: 1 AN: 1187518 Hom.: 0 Cov.: 30 AF XY: 0.00000174 AC XY: 1 AN XY: 574968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151204 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73854

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.16
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.068	T
Polyphen		0.99	D
Vest4		0.31
MutPred		0.40		Gain of catalytic residue at H23 (P = 0.0857);
MVP		0.82
ClinPred		0.90	D
GERP RS		2.9
Varity_R		0.39
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs745788400; hg19: chr13-100634401;