15-92997085-GA-GAA

Variant names:

• chr15-92997085-G-GA
• rs752940775
• ENST00000394196.9:c.3723dupA

Variant summary

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

The ENST00000394196.9(CHD2):​c.3723dupA​(p.Glu1242IlefsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,369,822 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 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (0 hom.)
• Consequence: CHD2 ENST00000394196.9 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.89
• Publications: 6 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 15-92997085-G-GA is Pathogenic according to our data. Variant chr15-92997085-G-GA is described in ClinVar as Pathogenic. ClinVar VariationId is 803141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD2	NM_001271.4	c.3734dupA		splice_donor_variant, intron_variant	Intron 29 of 38	ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.3723dupA	p.Glu1242IlefsTer13	frameshift_variant	Exon 29 of 39	5	NM_001271.4	ENSP00000377747.4
CHD2	ENST00000637789.1	n.*298dupA		non_coding_transcript_exon_variant	Exon 6 of 9	5		ENSP00000489767.1
CHD2	ENST00000637789.1	n.*298dupA		3_prime_UTR_variant	Exon 6 of 9	5		ENSP00000489767.1

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 147966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000248

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: 0.000106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0110 AC: 1720 AN: 156052 AF XY: 0.0106

Gnomad AFR exome AF: 0.00838

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.0121

Gnomad FIN exome AF: 0.00828

Gnomad NFE exome AF: 0.00850

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.00363 AC: 4436 AN: 1221856 Hom.: 0 Cov.: 32 AF XY: 0.00375 AC XY: 2271 AN XY: 606408

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

African (AFR) AF: 0.00564 AC: 150 AN: 26590

American (AMR) AF: 0.0113 AC: 363 AN: 32050

Ashkenazi Jewish (ASJ) AF: 0.00647 AC: 134 AN: 20716

East Asian (EAS) AF: 0.00437 AC: 144 AN: 32974

South Asian (SAS) AF: 0.00593 AC: 392 AN: 66092

European-Finnish (FIN) AF: 0.00441 AC: 199 AN: 45162

Middle Eastern (MID) AF: 0.00367 AC: 18 AN: 4902

European-Non Finnish (NFE) AF: 0.00302 AC: 2854 AN: 943652

Other (OTH) AF: 0.00366 AC: 182 AN: 49718

⚠️ 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 AF: 0.0000135 AC: 2 AN: 147966 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 71978

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

African (AFR) AF: 0.0000248 AC: 1 AN: 40334

American (AMR) AF: 0.00 AC: 0 AN: 14912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4682

European-Finnish (FIN) AF: 0.000106 AC: 1 AN: 9470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66790

Other (OTH) AF: 0.00 AC: 0 AN: 2040

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00795 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=0/200	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: COSV67707365; COSMIC: COSV67707365;