14-21385759-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001170629.2(CHD8):c.7600C>A(p.Leu2534Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L2534L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CHD8 NM_001170629.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CHD8
• BP4: Computational evidence support a benign effect (MetaRNN=0.23434123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD8	NM_001170629.2	c.7600C>A	p.Leu2534Met	missense_variant	38/38	ENST00000646647.2
LOC107984643	XR_001750627.2	n.441+1046G>T		intron_variant, non_coding_transcript_variant
CHD8	NM_020920.4	c.6763C>A	p.Leu2255Met	missense_variant	38/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD8	ENST00000646647.2	c.7600C>A	p.Leu2534Met	missense_variant	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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2534 of the CHD8 protein (p.Leu2534Met). 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. ClinVar contains an entry for this variant (Variation ID: 1716512). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	Benign	0.097
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.23	T;T;T;T;T;T
MetaSVM	Uncertain	-0.075	T
MutationTaster	Benign	0.95	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.030	N;N;.;.;N;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0080	D;D;.;.;D;.
Sift4G	Benign	0.15	T;T;.;.;T;.
Polyphen		0.89	P;.;.;P;.;.
Vest4		0.31
MutPred		0.20		.;Loss of catalytic residue at L2534 (P = 0.0091);Loss of catalytic residue at L2534 (P = 0.0091);.;Loss of catalytic residue at L2534 (P = 0.0091);Loss of catalytic residue at L2534 (P = 0.0091);
MVP		0.42
MPC		0.72
ClinPred		0.68	D
GERP RS		4.4
Varity_R		0.19
gMVP		0.19

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: chr14-21853918;