14-21385639-C-T

Variant names:

• chr14-21385639-C-T
• NM_001170629.2:c.7720G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001170629.2(CHD8):​c.7720G>A​(p.Asp2574Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHD8 NM_001170629.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.46

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
• PP2: Missense variant in the CHD8 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 18 curated pathogenic missense variants (we use a threshold of 10). The gene has 51 curated benign missense variants. Trascript score misZ: 7.0202 (above the threshold of 3.09). GenCC associations: The gene is linked to autism, intellectual disability, intellectual developmental disorder with autism and macrocephaly, congenital myasthenic syndrome, complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27963042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD8	NM_001170629.2	c.7720G>A	p.Asp2574Asn	missense_variant	Exon 38 of 38	ENST00000646647.2	NP_001164100.1
CHD8	NM_020920.4	c.6883G>A	p.Asp2295Asn	missense_variant	Exon 38 of 38		NP_065971.2
LOC107984643	XR_001750627.2	n.441+926C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD8	ENST00000646647.2	c.7720G>A	p.Asp2574Asn	missense_variant	Exon 38 of 38		NM_001170629.2	ENSP00000495240.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Feb 15, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jan 22, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with asparagine at codon 2574 of the CHD8 protein (p.Asp2574Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHD8-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;T;T;.;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	.;D;.;D;.;.
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	0.0	.;N;N;.;N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.67	N;N;.;.;N;.
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;.;.;D;.
Sift4G	Benign	0.32	T;T;.;.;T;.
Polyphen		0.88	P;.;.;P;.;.
Vest4		0.32
MutPred		0.17		.;Gain of glycosylation at S2573 (P = 0.1051);Gain of glycosylation at S2573 (P = 0.1051);.;Gain of glycosylation at S2573 (P = 0.1051);Gain of glycosylation at S2573 (P = 0.1051);
MVP		0.46
MPC		0.62
ClinPred		0.67	D
GERP RS		5.3
Varity_R		0.45
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-21853798;