NM_001271.4:c.2785_2801delGCCAAAAAGAAGATGGTinsTG

Variant names:

• chr15-92979192-GCCAAAAAGAAGATGGT-TG
• rs1555442889
• NM_001271.4:c.2785_2801delGCCAAAAAGAAGATGGTinsTG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001271.4(CHD2):​c.2785_2801delGCCAAAAAGAAGATGGTinsTG​(p.Ala929_Val934delinsTer) variant causes a stop gained, missense, disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHD2 NM_001271.4 stop_gained, missense, disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.89
• Publications: 0 publications found

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]

CHD2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 94

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-92979192-GCCAAAAAGAAGATGGT-TG is Pathogenic according to our data. Variant chr15-92979192-GCCAAAAAGAAGATGGT-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 541361.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271.4. 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
	CHD2	NM_001271.4	MANE Select	c.2785_2801delGCCAAAAAGAAGATGGTinsTG	p.Ala929_Val934delinsTer	stop_gained missense disruptive_inframe_deletion	N/A	NP_001262.3	O14647-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD2	ENST00000394196.9	TSL:5 MANE Select	c.2785_2801delGCCAAAAAGAAGATGGTinsTG	p.Ala929_Val934delinsTer	stop_gained missense disruptive_inframe_deletion	N/A	ENSP00000377747.4	O14647-1
	CHD2	ENST00000626874.2	TSL:1	c.2785_2801delGCCAAAAAGAAGATGGTinsTG	p.Ala929_Val934delinsTer	stop_gained missense disruptive_inframe_deletion	N/A	ENSP00000486629.1	O14647-2
	CHD2	ENST00000625463.1	TSL:1	c.325_*1delGCCAAAAAGAAGATGGTinsTG	p.Ala109fs	frameshift missense splice_region	Exon 4 of 4	ENSP00000486391.1	A0A0D9SF92

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy 94 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

Splicing

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

Other links and lift over

dbSNP: rs1555442889; hg19: chr15-93522422;