NM_205768.3:c.599delC

Variant names:

• chr1-244054372-TC-T
• rs1060499655
• NM_205768.3:c.599delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_205768.3(ZBTB18):​c.599delC​(p.Ser200fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB18 NM_205768.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.11
• Publications: 1 publications found

Genes affected

ZBTB18 (HGNC:13030): (zinc finger and BTB domain containing 18) This gene encodes a C2H2-type zinc finger protein which acts a transcriptional repressor of genes involved in neuronal development. The encoded protein recognizes a specific sequence motif and recruits components of chromatin to target genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ZBTB18 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 22

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 57 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-244054372-TC-T is Pathogenic according to our data. Variant chr1-244054372-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 397517.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_205768.3. 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
	ZBTB18	NM_205768.3	MANE Select	c.599delC	p.Ser200fs	frameshift	Exon 2 of 2	NP_991331.1
	ZBTB18	NM_001278196.2		c.572delC	p.Ser191fs	frameshift	Exon 2 of 2	NP_001265125.1
	ZBTB18	NM_006352.5		c.572delC	p.Ser191fs	frameshift	Exon 1 of 1	NP_006343.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB18	ENST00000358704.4	TSL:1 MANE Select	c.599delC	p.Ser200fs	frameshift	Exon 2 of 2	ENSP00000351539.4
	ZBTB18	ENST00000914124.1		c.599delC	p.Ser200fs	frameshift	Exon 3 of 3	ENSP00000584183.1
	ZBTB18	ENST00000622512.1	TSL:3	c.572delC	p.Ser191fs	frameshift	Exon 2 of 2	ENSP00000481278.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, autosomal dominant 22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs1060499655; hg19: chr1-244217674;