rs1831992

Variant names:

• chr13-99983123-C-T
• rs1831992
• NM_007129.5:c.1059C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_007129.5(ZIC2):​c.1059C>T​(p.His353His) variant causes a synonymous change. The variant allele was found at a frequency of 0.0996 in 1,613,394 control chromosomes in the GnomAD database, including 9,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (591 hom., cov: 31)
  • Exomes 𝑓: 0.10 (8583 hom.)
• Consequence: ZIC2 NM_007129.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.17
• Publications: 15 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 13-99983123-C-T is Benign according to our data. Variant chr13-99983123-C-T is described in ClinVar as Benign. ClinVar VariationId is 95446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC2	NM_007129.5	c.1059C>T	p.His353His	synonymous_variant	Exon 1 of 3	ENST00000376335.8	NP_009060.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZIC2	ENST00000376335.8	c.1059C>T	p.His353His	synonymous_variant	Exon 1 of 3	1	NM_007129.5	ENSP00000365514.3

Frequencies

GnomAD3 genomes AF: 0.0774 AC: 11752 AN: 151764 Hom.: 592 Cov.: 31

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.000781

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.0821

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0979

GnomAD2 exomes AF: 0.0812 AC: 20362 AN: 250680 AF XY: 0.0823

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.0607

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0847

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.102 AC: 148931 AN: 1461510 Hom.: 8583 Cov.: 35 AF XY: 0.100 AC XY: 72787 AN XY: 727066

African (AFR) AF: 0.0163 AC: 547 AN: 33464

American (AMR) AF: 0.0640 AC: 2861 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4418 AN: 26104

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39698

South Asian (SAS) AF: 0.0297 AC: 2563 AN: 86252

European-Finnish (FIN) AF: 0.0889 AC: 4737 AN: 53282

Middle Eastern (MID) AF: 0.105 AC: 608 AN: 5768

European-Non Finnish (NFE) AF: 0.114 AC: 127133 AN: 1111884

Other (OTH) AF: 0.100 AC: 6056 AN: 60384

GnomAD4 genome AF: 0.0774 AC: 11750 AN: 151884 Hom.: 591 Cov.: 31 AF XY: 0.0748 AC XY: 5556 AN XY: 74240

African (AFR) AF: 0.0205 AC: 848 AN: 41434

American (AMR) AF: 0.0880 AC: 1343 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 564 AN: 3464

East Asian (EAS) AF: 0.000782 AC: 4 AN: 5112

South Asian (SAS) AF: 0.0279 AC: 134 AN: 4802

European-Finnish (FIN) AF: 0.0821 AC: 869 AN: 10588

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7647 AN: 67914

Other (OTH) AF: 0.0964 AC: 203 AN: 2106

Alfa AF: 0.0842 Hom.: 602

Bravo AF: 0.0757

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.126

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jul 08, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Holoprosencephaly 5 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.66
PhyloP100		6.2
Mutation Taster		=33/67	polymorphism (auto)

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: rs1831992; hg19: chr13-100635377;