14-21385709-T-A

Position:

• chr14-21385709-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Moderate BS2

The NM_001170629.2(CHD8):​c.7650A>T​(p.Leu2550Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,399,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CHD8 NM_001170629.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD8. . Trascript score misZ 7.0202 (greater than threshold 3.09). GenCC has associacion of gene with autism, intellectual disability, intellectual developmental disorder with autism and macrocephaly, congenital myasthenic syndrome, complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23923242).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD8	NM_001170629.2	c.7650A>T	p.Leu2550Phe	missense_variant	38/38	ENST00000646647.2
LOC107984643	XR_001750627.2	n.441+996T>A		intron_variant, non_coding_transcript_variant
CHD8	NM_020920.4	c.6813A>T	p.Leu2271Phe	missense_variant	38/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD8	ENST00000646647.2	c.7650A>T	p.Leu2550Phe	missense_variant	38/38		NM_001170629.2	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1399652 Hom.: 0 Cov.: 35 AF XY: 0.00000145 AC XY: 1 AN XY: 690320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000689

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

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. 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"). This variant has not been reported in the literature in individuals affected with CHD8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2550 of the CHD8 protein (p.Leu2550Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;T;.;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.88	.;D;.;D;.;.
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.34	.;N;N;.;N;N
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;N;.;.;N;.
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;.;.;D;.
Sift4G	Benign	0.099	T;T;.;.;T;.
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.37
MutPred		0.13		.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.61
MPC		0.71
ClinPred		0.79	D
GERP RS		5.3
Varity_R		0.33
gMVP		0.24

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: rs1887192182; hg19: chr14-21853868;