15-93002203-GAAAA-GAAAAAA

Variant names:

• chr15-93002203-G-GAA
• rs749969667
• NM_001271.4:c.4172_4173dupAA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001271.4(CHD2):​c.4172_4173dupAA​(p.Gln1392AsnfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000036 in 1,389,612 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CHD2 NM_001271.4 frameshift
• Clinical Significance: Not reported in ClinVar
• 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 10 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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD2	NM_001271.4	MANE Select	c.4172_4173dupAA	p.Gln1392AsnfsTer15	frameshift	Exon 33 of 39	NP_001262.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD2	ENST00000394196.9	TSL:5 MANE Select	c.4172_4173dupAA	p.Gln1392AsnfsTer15	frameshift	Exon 33 of 39	ENSP00000377747.4
	CHD2	ENST00000626874.2	TSL:1	c.4172_4173dupAA	p.Gln1392AsnfsTer15	frameshift	Exon 33 of 38	ENSP00000486629.1
	CHD2	ENST00000625662.3	TSL:5	n.*343_*344dupAA		non_coding_transcript_exon	Exon 29 of 35	ENSP00000486007.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000553 AC: 1 AN: 180784 AF XY: 0.0000102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000360 AC: 5 AN: 1389612 Hom.: 0 Cov.: 30 AF XY: 0.00000725 AC XY: 5 AN XY: 690070

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

African (AFR) AF: 0.00 AC: 0 AN: 30056

American (AMR) AF: 0.00 AC: 0 AN: 36000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24184

East Asian (EAS) AF: 0.00 AC: 0 AN: 37244

South Asian (SAS) AF: 0.0000261 AC: 2 AN: 76538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5474

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1072206

Other (OTH) AF: 0.0000176 AC: 1 AN: 56922

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=2/198	disease causing (fs/PTC)

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;