14-21409898-G-C

Variant names:

• chr14-21409898-G-C
• rs776631057
• NM_001170629.2:c.2317C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001170629.2(CHD8):​c.2317C>G​(p.Arg773Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R773Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CHD8 NM_001170629.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20503944).
• BS2: High AC in GnomAdExome4 at 24 AD gene.

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.2317C>G	p.Arg773Gly	missense	Exon 11 of 38	NP_001164100.1	Q9HCK8-1
	CHD8	NM_020920.4		c.1480C>G	p.Arg494Gly	missense	Exon 11 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.2317C>G	p.Arg773Gly	missense	Exon 11 of 38	ENSP00000495240.1	Q9HCK8-1
	CHD8	ENST00000430710.8	TSL:1	c.1480C>G	p.Arg494Gly	missense	Exon 11 of 38	ENSP00000406288.3	Q9HCK8-2
	CHD8	ENST00000557364.6	TSL:5	c.2317C>G	p.Arg773Gly	missense	Exon 11 of 38	ENSP00000451601.1	Q9HCK8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249076 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461456 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 727012

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111730

Other (OTH) AF: 0.0000166 AC: 1 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
PhyloP100		1.6
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.45
Mutation Taster		=86/14	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs776631057; hg19: chr14-21878057;