NM_001170629.2:c.7620_7631delCGATGAGGATGA

Variant names:

• chr14-21385727-TTCATCCTCATCG-T
• rs1887193020
• NM_001170629.2:c.7620_7631delCGATGAGGATGA

Variant summary

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

The NM_001170629.2(CHD8):​c.7620_7631delCGATGAGGATGA​(p.Asp2540_Asp2543del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000143 in 1,399,606 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D2540D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHD8 NM_001170629.2 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.39
• Publications: 0 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

ENSG00000260830 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001170629.2

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD8	NM_001170629.2	MANE Select	c.7620_7631delCGATGAGGATGA	p.Asp2540_Asp2543del	disruptive_inframe_deletion	Exon 38 of 38	NP_001164100.1	Q9HCK8-1
	CHD8	NM_020920.4		c.6783_6794delCGATGAGGATGA	p.Asp2261_Asp2264del	disruptive_inframe_deletion	Exon 38 of 38	NP_065971.2	Q9HCK8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD8	ENST00000646647.2	MANE Select	c.7620_7631delCGATGAGGATGA	p.Asp2540_Asp2543del	disruptive_inframe_deletion	Exon 38 of 38	ENSP00000495240.1	Q9HCK8-1
	CHD8	ENST00000430710.8	TSL:1	c.6783_6794delCGATGAGGATGA	p.Asp2261_Asp2264del	disruptive_inframe_deletion	Exon 38 of 38	ENSP00000406288.3	Q9HCK8-2
	CHD8	ENST00000557364.6	TSL:5	c.7620_7631delCGATGAGGATGA	p.Asp2540_Asp2543del	disruptive_inframe_deletion	Exon 38 of 38	ENSP00000451601.1	Q9HCK8-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399606 Hom.: 0 AF XY: 0.00000145 AC XY: 1 AN XY: 690312

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

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079006

Other (OTH) AF: 0.00 AC: 0 AN: 58056

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4

Splicing

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

Other links and lift over

dbSNP: rs1887193020; hg19: chr14-21853886;