rs1555437851

chr15-92929038-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PP5_Moderate BP4 BP7

The NM_001271.4(CHD2):c.390C>T(p.Ser130=) variant causes a synonymous 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHD2 NM_001271.4 synonymous
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.619

Genes affected

CHD2 (HGNC:1917): (chromodomain helicase DNA binding protein 2) The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-92929038-C-T is Pathogenic according to our data. Variant chr15-92929038-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 474387.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).. Strength limited to SUPPORTING due to the PP5.
• BP7: Synonymous conserved (PhyloP=0.619 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD2	NM_001271.4	c.390C>T	p.Ser130=	synonymous_variant	5/39	ENST00000394196.9
CHD2	NM_001042572.3	c.390C>T	p.Ser130=	synonymous_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD2	ENST00000394196.9	c.390C>T	p.Ser130=	synonymous_variant	5/39	5	NM_001271.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459304 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725702

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 94 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 28, 2019

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to arise de novo in an individual affected with Lennox Gastaut Syndrome (LGS) (PMID: 25262651). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 130 of the CHD2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CHD2 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
Cadd	Benign	16
Dann	Benign	0.75
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555437851; hg19: chr15-93472268;