15-93002203-GAAAA-GAAAAA

Variant names:

• chr15-93002203-G-GA
• rs749969667
• NM_001271.4:c.4173dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001271.4(CHD2):​c.4173dupA​(p.Gln1392ThrfsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.00256 in 1,350,322 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHD2 NM_001271.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 4.43
• Publications: 3 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-93002203-G-GA is Pathogenic according to our data. Variant chr15-93002203-G-GA is described in ClinVar as Pathogenic. ClinVar VariationId is 218395.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.4173dupA	p.Gln1392ThrfsTer17	frameshift	Exon 33 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.4173dupA	p.Gln1392ThrfsTer17	frameshift	Exon 33 of 39	ENSP00000377747.4	O14647-1
	CHD2	ENST00000626874.2	TSL:1	c.4173dupA	p.Gln1392ThrfsTer17	frameshift	Exon 33 of 38	ENSP00000486629.1	O14647-2
	CHD2	ENST00000625662.3	TSL:5	n.*344dupA		non_coding_transcript_exon	Exon 29 of 35	ENSP00000486007.2	A0A0D9SEU0

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 147818 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00417 AC: 753 AN: 180784 AF XY: 0.00398

Gnomad AFR exome AF: 0.00521

Gnomad AMR exome AF: 0.00880

Gnomad ASJ exome AF: 0.00522

Gnomad EAS exome AF: 0.00671

Gnomad FIN exome AF: 0.00169

Gnomad NFE exome AF: 0.00288

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00256 AC: 3458 AN: 1350322 Hom.: 0 Cov.: 30 AF XY: 0.00257 AC XY: 1724 AN XY: 670148

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00369 AC: 108 AN: 29242

American (AMR) AF: 0.00615 AC: 215 AN: 34974

Ashkenazi Jewish (ASJ) AF: 0.00252 AC: 59 AN: 23406

East Asian (EAS) AF: 0.00263 AC: 95 AN: 36096

South Asian (SAS) AF: 0.00307 AC: 226 AN: 73602

European-Finnish (FIN) AF: 0.00125 AC: 62 AN: 49494

Middle Eastern (MID) AF: 0.000936 AC: 5 AN: 5344

European-Non Finnish (NFE) AF: 0.00248 AC: 2587 AN: 1042968

Other (OTH) AF: 0.00183 AC: 101 AN: 55196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 147912 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71982

African (AFR) AF: 0.00 AC: 0 AN: 40260

American (AMR) AF: 0.00 AC: 0 AN: 14870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66724

Other (OTH) AF: 0.00 AC: 0 AN: 2048

Alfa AF: 0.00335 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Developmental and epileptic encephalopathy 94 (6)
1	-	-	CHD2-related disorder (2)
1	-	-	Complex neurodevelopmental disorder (1)
1	-	-	not provided (1)
1	-	-	Seizure;C0856975:Autistic behavior (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs749969667; hg19: chr15-93545433; COSMIC: COSV67706917; COSMIC: COSV67706917;