rs1372483405

Variant names:

• chr14-21385712-GTCA-G
• rs1372483405
• NM_001170629.2:c.7644_7646delTGA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001170629.2(CHD8):​c.7644_7646delTGA​(p.Asp2549del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000714 in 1,399,640 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: CHD8 NM_001170629.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.40

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 14-21385712-GTCA-G is Benign according to our data. Variant chr14-21385712-GTCA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2429995.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD8	NM_001170629.2	c.7644_7646delTGA	p.Asp2549del	disruptive_inframe_deletion	Exon 38 of 38	ENST00000646647.2	NP_001164100.1
CHD8	NM_020920.4	c.6807_6809delTGA	p.Asp2270del	disruptive_inframe_deletion	Exon 38 of 38		NP_065971.2
LOC107984643	XR_001750627.2	n.441+1008_441+1010delATC		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD8	ENST00000646647.2	c.7644_7646delTGA	p.Asp2549del	disruptive_inframe_deletion	Exon 38 of 38		NM_001170629.2	ENSP00000495240.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000714 AC: 10 AN: 1399640 Hom.: 0 AF XY: 0.00000869 AC XY: 6 AN XY: 690318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.0000405

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Feb 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.7644_7646del, results in the deletion of 1 amino acid(s) of the CHD8 protein (p.Asp2549del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHD8-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Autism spectrum disorder Benign:1

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Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1372483405; hg19: chr14-21853871;