chr13-99982141-C-G

Position:

• chr13-99982141-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007129.5(ZIC2):​c.77C>G​(p.Ala26Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZIC2 NM_007129.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.61

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16146141).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC2	NM_007129.5	c.77C>G	p.Ala26Gly	missense_variant	1/3	ENST00000376335.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC2	ENST00000376335.8	c.77C>G	p.Ala26Gly	missense_variant	1/3	1	NM_007129.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holoprosencephaly 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 26 of the ZIC2 protein (p.Ala26Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ZIC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2244731). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.77C>G (p.A26G) alteration is located in exon 1 (coding exon 1) of the ZIC2 gene. This alteration results from a C to G substitution at nucleotide position 77, causing the alanine (A) at amino acid position 26 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.070	N
REVEL	Benign	0.059
Sift	Benign	0.47	T
Sift4G	Benign	0.49	T
Polyphen		0.34	B
Vest4		0.20
MutPred		0.33		Gain of catalytic residue at A26 (P = 0.0017);
MVP		0.81
ClinPred		0.58	D
GERP RS		3.1
Varity_R		0.089
gMVP		0.25

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: chr13-100634395;