13-99982753-CCCACCACCACCACCACCACCA-CCCACCACCACCACCACCACCACCA

Variant names:

• chr13-99982753-C-CCCA
• rs398124241
• NM_007129.5:c.716_718dupACC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_007129.5(ZIC2):​c.716_718dupACC​(p.His239dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,596,576 control chromosomes in the GnomAD database, including 414 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (184 hom., cov: 31)
  • Exomes 𝑓: 0.011 (230 hom.)
• Consequence: ZIC2 NM_007129.5 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.159
• Publications: 4 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_007129.5
• BP6: Variant 13-99982753-C-CCCA is Benign according to our data. Variant chr13-99982753-C-CCCA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

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.716_718dupACC	p.His239dup	disruptive_inframe_insertion	Exon 1 of 3	NP_009060.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC2	ENST00000376335.8	TSL:1 MANE Select	c.716_718dupACC	p.His239dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000365514.3	O95409

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4936 AN: 151396 Hom.: 186 Cov.: 31

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0702

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.0604

Gnomad SAS AF: 0.0343

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.0279

GnomAD2 exomes AF: 0.0389 AC: 7641 AN: 196444 AF XY: 0.0341

Gnomad AFR exome AF: 0.0841

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.000678

Gnomad EAS exome AF: 0.0790

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.00264

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0111 AC: 15982 AN: 1445066 Hom.: 230 Cov.: 31 AF XY: 0.0111 AC XY: 7972 AN XY: 719210

African (AFR) AF: 0.0708 AC: 2358 AN: 33326

American (AMR) AF: 0.109 AC: 4831 AN: 44434

Ashkenazi Jewish (ASJ) AF: 0.000538 AC: 14 AN: 26020

East Asian (EAS) AF: 0.0796 AC: 3143 AN: 39474

South Asian (SAS) AF: 0.0334 AC: 2873 AN: 86024

European-Finnish (FIN) AF: 0.0114 AC: 476 AN: 41804

Middle Eastern (MID) AF: 0.00505 AC: 29 AN: 5742

European-Non Finnish (NFE) AF: 0.00129 AC: 1434 AN: 1108274

Other (OTH) AF: 0.0137 AC: 824 AN: 59968

GnomAD4 genome AF: 0.0327 AC: 4951 AN: 151510 Hom.: 184 Cov.: 31 AF XY: 0.0352 AC XY: 2602 AN XY: 74012

African (AFR) AF: 0.0741 AC: 3062 AN: 41300

American (AMR) AF: 0.0702 AC: 1067 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.0606 AC: 309 AN: 5100

South Asian (SAS) AF: 0.0335 AC: 160 AN: 4776

European-Finnish (FIN) AF: 0.0156 AC: 164 AN: 10536

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 67824

Other (OTH) AF: 0.0296 AC: 62 AN: 2098

Alfa AF: 0.00293 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Holoprosencephaly 5 (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=75/25	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs398124241; hg19: chr13-100635007; COSMIC: COSV66255470; COSMIC: COSV66255470;