13-99982147-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_007129.5(ZIC2):​c.83C>T​(p.Ala28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000842 in 1,187,516 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. A28G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 8.4e-7 ( 0 hom. )

Consequence

ZIC2
NM_007129.5 missense

Scores

2
2
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.05
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.41056296).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZIC2NM_007129.5 linkc.83C>T p.Ala28Val missense_variant Exon 1 of 3 ENST00000376335.8 NP_009060.2 O95409A0A024RDY6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZIC2ENST00000376335.8 linkc.83C>T p.Ala28Val missense_variant Exon 1 of 3 1 NM_007129.5 ENSP00000365514.3 O95409

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
8.42e-7
AC:
1
AN:
1187516
Hom.:
0
Cov.:
30
AF XY:
0.00000174
AC XY:
1
AN XY:
574968
show subpopulations
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:
0.00000102
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.49
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T
Eigen
Benign
0.10
Eigen_PC
Benign
0.059
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.66
T
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.41
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N
PrimateAI
Pathogenic
0.92
D
PROVEAN
Benign
-0.12
N
REVEL
Benign
0.11
Sift
Benign
0.15
T
Sift4G
Benign
0.21
T
Polyphen
1.0
D
Vest4
0.30
MutPred
0.41
Gain of catalytic residue at A28 (P = 0);
MVP
0.80
ClinPred
0.84
D
GERP RS
2.9
Varity_R
0.12
gMVP
0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-100634401; API