13-99982141-C-T

Variant names:

• chr13-99982141-C-T
• rs1402597881
• NM_007129.5:c.77C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_007129.5(ZIC2):​c.77C>T​(p.Ala26Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000541 in 1,294,866 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A26G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: ZIC2 NM_007129.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61
• 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 -1 ACMG points.

• 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=0.16094136).

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.77C>T	p.Ala26Val	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.77C>T	p.Ala26Val	missense	Exon 1 of 3	ENSP00000365514.3	O95409

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150712 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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000437 AC: 5 AN: 1144154 Hom.: 0 Cov.: 30 AF XY: 0.00000364 AC XY: 2 AN XY: 549528

African (AFR) AF: 0.00 AC: 0 AN: 23086

American (AMR) AF: 0.00 AC: 0 AN: 9906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15744

East Asian (EAS) AF: 0.00 AC: 0 AN: 26440

South Asian (SAS) AF: 0.0000272 AC: 1 AN: 36826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3870

European-Non Finnish (NFE) AF: 0.00000418 AC: 4 AN: 956798

Other (OTH) AF: 0.00 AC: 0 AN: 46100

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150712 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73552

African (AFR) AF: 0.00 AC: 0 AN: 41188

American (AMR) AF: 0.00 AC: 0 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5084

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67532

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.081
Sift	Uncertain	0.010	D
Sift4G	Benign	0.41	T
Polyphen		0.0020	B
Vest4		0.25
MVP		0.77
ClinPred		0.75	D
GERP RS		3.1
PromoterAI		0.018	Neutral
Varity_R		0.12
gMVP		0.38
Mutation Taster		=91/9	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: rs1402597881; hg19: chr13-100634395;