rs1555445685

Variant names:

• chr15-93014769-ACT-A
• rs1555445685
• NM_001271.4:c.4771_4772delCT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001271.4(CHD2):​c.4771_4772delCT​(p.Leu1591AspfsTer32) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD2 NM_001271.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.43
• 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-93014769-ACT-A is Pathogenic according to our data. Variant chr15-93014769-ACT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 521424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.4771_4772delCT	p.Leu1591AspfsTer32	frameshift	Exon 37 of 39	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.4771_4772delCT	p.Leu1591AspfsTer32	frameshift	Exon 37 of 39	ENSP00000377747.4	O14647-1
	CHD2	ENST00000626874.2	TSL:1	c.4771_4772delCT	p.Leu1591AspfsTer32	frameshift	Exon 37 of 38	ENSP00000486629.1	O14647-2
	CHD2	ENST00000625662.3	TSL:5	n.*942_*943delCT		non_coding_transcript_exon	Exon 33 of 35	ENSP00000486007.2	A0A0D9SEU0

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	CHD2-related disorder (1)
1	-	-	Developmental and epileptic encephalopathy 94 (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555445685; hg19: chr15-93557999;