13-99982115-C-G

Variant names:

• chr13-99982115-C-G
• rs758647169
• NM_007129.5:c.51C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_007129.5(ZIC2):​c.51C>G​(p.Phe17Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000876 in 1,141,650 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F17F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: ZIC2 NM_007129.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49
• 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 3 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.

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.51C>G	p.Phe17Leu	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.51C>G	p.Phe17Leu	missense	Exon 1 of 3	ENSP00000365514.3	O95409

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.76e-7 AC: 1 AN: 1141650 Hom.: 0 Cov.: 30 AF XY: 0.00000183 AC XY: 1 AN XY: 547544

African (AFR) AF: 0.00 AC: 0 AN: 23154

American (AMR) AF: 0.00 AC: 0 AN: 8980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15352

East Asian (EAS) AF: 0.00 AC: 0 AN: 26666

South Asian (SAS) AF: 0.00 AC: 0 AN: 34924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3620

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 957342

Other (OTH) AF: 0.00 AC: 0 AN: 46278

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.5
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.42	T
Polyphen		0.99	D
Vest4		0.50
MutPred		0.46		Gain of catalytic residue at V14 (P = 0)
MVP		0.85
ClinPred		0.91	D
GERP RS		2.3
PromoterAI		0.014	Neutral
Varity_R		0.51
gMVP		0.41
Mutation Taster		=52/48	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

dbSNP: rs758647169; hg19: chr13-100634369;