Genetic Variant NM_007129.5:c.1386_1406delGGCGGCTGCGGCGGCGGCGGC (chr13-99985460-AGCGGCGGCGGCGGCTGCGGCG-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_007129.5(ZIC2):c.1386_1406delGGCGGCTGCGGCGGCGGCGGC(p.Ala463_Ala469del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000189 in 1,375,446 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A462A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 1 hom. )

Consequence

ZIC2
NM_007129.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.97

Publications

0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P
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: Likely_benign. The variant received -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_007129.5

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.1386_1406delGGCGGCTGCGGCGGCGGCGGC	p.Ala463_Ala469del	disruptive_inframe_deletion	Exon 3 of 3	NP_009060.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZIC2	ENST00000376335.8	TSL:1 MANE Select	c.1386_1406delGGCGGCTGCGGCGGCGGCGGC	p.Ala463_Ala469del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000365514.3	O95409
ZIC2	ENST00000468291.1	TSL:2	n.360_380delGGCGGCTGCGGCGGCGGCGGC		non_coding_transcript_exon	Exon 3 of 3
ZIC2	ENST00000477213.1	TSL:2	n.468_*15delGGCGGCTGCGGCGGCGGCGGC		splice_region non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

149586

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

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:

0.00

Gnomad OTH

AF:

0.000488

GnomAD2 exomes

AF:

0.0000750

AC:

AN:

93320

AF XY:

0.0000540

show subpopulations

Gnomad AFR exome

AF:

0.000251

Gnomad AMR exome

AF:

0.000357

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000607

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000188

AC:

AN:

1225762

Hom.:

AF XY:

0.0000183

AC XY:

AN XY:

600918

show subpopulations

African (AFR)

AF:

0.0000792

AC:

AN:

25248

American (AMR)

AF:

0.000110

AC:

AN:

18246

Ashkenazi Jewish (ASJ)

AF:

0.0000517

AC:

AN:

19342

East Asian (EAS)

AF:

0.00

AC:

AN:

29576

South Asian (SAS)

AF:

0.0000218

AC:

AN:

45862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27714

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4760

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

1005134

Other (OTH)

AF:

0.0000802

AC:

AN:

49880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.561

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000200

AC:

AN:

149684

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

73030

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41056

American (AMR)

AF:

0.0000664

AC:

AN:

15060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3440

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67214

Other (OTH)

AF:

0.000483

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

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

6.0

Mutation Taster

=133/67

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over