Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3BP6_ModerateBS2

The NM_007129.5(ZIC2):c.716_718delACC(p.His239del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000553 in 1,569,796 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00058 ( 2 hom. )

Consequence

ZIC2
NM_007129.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.159

Publications

4 publications found

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]

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

ZIC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_007129.5

BP6

Variant 13-99982753-CCCA-C is Benign according to our data. Variant chr13-99982753-CCCA-C is described in ClinVar as Benign. ClinVar VariationId is 1658523.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC2	NM_007129.5	MANE Select	c.716_718delACC	p.His239del	disruptive_inframe_deletion	Exon 1 of 3	NP_009060.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC2	ENST00000376335.8	TSL:1 MANE Select	c.716_718delACC	p.His239del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000365514.3

Frequencies

GnomAD3 genomes

AF:

0.000284

AC:

AN:

151380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000364

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000391

Gnomad SAS

AF:

0.000628

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.000251

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00256

AC:

502

AN:

196444

AF XY:

0.00245

show subpopulations

Gnomad AFR exome

AF:

0.00330

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.000903

Gnomad EAS exome

AF:

0.00207

Gnomad FIN exome

AF:

0.00581

Gnomad NFE exome

AF:

0.00303

Gnomad OTH exome

AF:

0.00176

GnomAD4 exome

AF:

0.000582

AC:

826

AN:

1418302

Hom.:

AF XY:

0.000625

AC XY:

440

AN XY:

704398

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000398

AC:

AN:

32664

American (AMR)

AF:

0.00110

AC:

AN:

42914

Ashkenazi Jewish (ASJ)

AF:

0.000198

AC:

AN:

25296

East Asian (EAS)

AF:

0.000496

AC:

AN:

38292

South Asian (SAS)

AF:

0.000916

AC:

AN:

82952

European-Finnish (FIN)

AF:

0.00238

AC:

AN:

40304

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.000478

AC:

522

AN:

1091466

Other (OTH)

AF:

0.000800

AC:

AN:

58744

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

106

160

213

266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000277

AC:

AN:

151494

Hom.:

Cov.:

AF XY:

0.000297

AC XY:

AN XY:

74002

show subpopulations

African (AFR)

AF:

0.000363

AC:

AN:

41308

American (AMR)

AF:

0.000263

AC:

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000392

AC:

AN:

5102

South Asian (SAS)

AF:

0.000628

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10524

Middle Eastern (MID)

AF:

0.00345

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000251

AC:

AN:

67816

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00719

Hom.:

Bravo

AF:

0.000261

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holoprosencephaly 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.16

Mutation Taster

=74/26

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over