13-99982078-C-T

Variant names:

• chr13-99982078-C-T
• NM_007129.5:c.14C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_007129.5(ZIC2):​c.14C>T​(p.Ala5Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000091 in 1,098,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: ZIC2 NM_007129.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.94
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.2124 (above the threshold of 3.09). Trascript score misZ: 0.4623 (below the threshold of 3.09). GenCC associations: The gene is linked to holoprosencephaly 5, holoprosencephaly.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3030616).

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.14C>T	p.Ala5Val	missense	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.14C>T	p.Ala5Val	missense	Exon 1 of 3	ENSP00000365514.3	O95409

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.10e-7 AC: 1 AN: 1098726 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 521928

African (AFR) AF: 0.00 AC: 0 AN: 22640

American (AMR) AF: 0.00 AC: 0 AN: 8212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14338

East Asian (EAS) AF: 0.00 AC: 0 AN: 26038

South Asian (SAS) AF: 0.00 AC: 0 AN: 24934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3076

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 932742

Other (OTH) AF: 0.00 AC: 0 AN: 44224

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

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
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.12
Sift	Benign	0.10	T
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.38
MutPred		0.30		Gain of catalytic residue at Q8 (P = 5e-04)
MVP		0.53
ClinPred		0.86	D
GERP RS		3.1
PromoterAI		-0.0076	Neutral
Varity_R		0.17
gMVP		0.40
Mutation Taster		=61/39	polymorphism

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

hg19: chr13-100634332;