15-92997085-GA-GAAA

Variant names:

• chr15-92997085-G-GAA
• rs752940775
• ENST00000394196.9:c.3722_3723dupAA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001271.4(CHD2):​c.3733_3734dupAA variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,315,774 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: CHD2 NM_001271.4 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.89
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

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.3733_3734dupAA		splice_donor intron	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.3722_3723dupAA	p.Glu1242AsnfsTer4	frameshift	Exon 29 of 39	ENSP00000377747.4	O14647-1
	CHD2	ENST00000626874.2	TSL:1	c.3722_3723dupAA	p.Glu1242AsnfsTer4	frameshift	Exon 29 of 38	ENSP00000486629.1	O14647-2
	CHD2	ENST00000628118.2	TSL:1	n.*991_*992dupAA		non_coding_transcript_exon	Exon 20 of 23	ENSP00000515059.1	A0A8V8TRB2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000256 AC: 4 AN: 156052 AF XY: 0.0000237

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000575

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000696

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.000302

GnomAD4 exome AF: 0.00000456 AC: 6 AN: 1315774 Hom.: 0 Cov.: 32 AF XY: 0.00000306 AC XY: 2 AN XY: 653466

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

African (AFR) AF: 0.0000349 AC: 1 AN: 28670

American (AMR) AF: 0.0000874 AC: 3 AN: 34312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22672

East Asian (EAS) AF: 0.00 AC: 0 AN: 35512

South Asian (SAS) AF: 0.0000138 AC: 1 AN: 72512

European-Finnish (FIN) AF: 0.0000208 AC: 1 AN: 48054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5174

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1015084

Other (OTH) AF: 0.00 AC: 0 AN: 53784

⚠️ 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		8.9
Mutation Taster		=1/199	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: rs752940775; hg19: chr15-93540315; COSMIC: COSV105335939;