14-21385727-T-TTCATCCTCATCG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001170629.2(CHD8):c.7631_7632insCGATGAGGATGA(p.Asp2540_Asp2543dup) variant causes a inframe insertion 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E2544E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CHD8 NM_001170629.2 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96

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]

LOC107984643 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD8	NM_001170629.2	c.7631_7632insCGATGAGGATGA	p.Asp2540_Asp2543dup	inframe_insertion	38/38	ENST00000646647.2
LOC107984643	XR_001750627.2	n.441+1023_441+1034dup		intron_variant, non_coding_transcript_variant
CHD8	NM_020920.4	c.6794_6795insCGATGAGGATGA	p.Asp2261_Asp2264dup	inframe_insertion	38/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD8	ENST00000646647.2	c.7631_7632insCGATGAGGATGA	p.Asp2540_Asp2543dup	inframe_insertion	38/38		NM_001170629.2	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with autism and macrocephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 23, 2024

Criteria applied: PM4,PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-21853886;