NM_001170629.2:c.347delC

Variant names:

• chr14-21431296-TG-T
• rs1135401763
• NM_001170629.2:c.347delC

Variant summary

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

The NM_001170629.2(CHD8):​c.347delC​(p.Thr116AsnfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD8 NM_001170629.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.67
• Publications: 1 publications found

Genes affected

CHD8 (HGNC:20153): (chromodomain helicase DNA binding protein 8) This gene encodes a member of the chromodomain-helicase-DNA binding protein family, which is characterized by a SNF2-like domain and two chromatin organization modifier domains. The encoded protein also contains brahma and kismet domains, which are common to the subfamily of chromodomain-helicase-DNA binding proteins to which this protein belongs. This gene has been shown to function in several processes that include transcriptional regulation, epigenetic remodeling, promotion of cell proliferation, and regulation of RNA synthesis. Allelic variants of this gene are associated with autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2016]

CHD8 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autism

  Inheritance: AD Classification: STRONG Submitted by: G2P
• intellectual developmental disorder with autism and macrocephaly

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• congenital myasthenic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-21431296-TG-T is Pathogenic according to our data. Variant chr14-21431296-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 431177.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170629.2. 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
	CHD8	NM_001170629.2	MANE Select	c.347delC	p.Thr116AsnfsTer14	frameshift	Exon 2 of 38	NP_001164100.1
	CHD8	NM_020920.4		c.6+514delC		intron	N/A	NP_065971.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD8	ENST00000646647.2	MANE Select	c.347delC	p.Thr116AsnfsTer14	frameshift	Exon 2 of 38	ENSP00000495240.1
	CHD8	ENST00000430710.8	TSL:1	c.6+514delC		intron	N/A	ENSP00000406288.3
	CHD8	ENST00000557364.6	TSL:5	c.347delC	p.Thr116AsnfsTer14	frameshift	Exon 2 of 38	ENSP00000451601.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with autism and macrocephaly Pathogenic:1

Aug 01, 2017

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

De novo LOF varaiant in a patient with mild ID, wide ventricles, constipation, social difficulties.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=0/200	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: rs1135401763; hg19: chr14-21899455;