15-93002203-GAAAA-GAAA

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001271.4(CHD2):​c.4173delA​(p.Lys1391AsnfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000137 in 1,389,718 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CHD2 NM_001271.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-93002203-GA-G is Pathogenic according to our data. Variant chr15-93002203-GA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 981296.

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.4173delA	p.Lys1391AsnfsTer15	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.4173delA	p.Lys1391AsnfsTer15	frameshift	Exon 33 of 39	ENSP00000377747.4	O14647-1
	CHD2	ENST00000626874.2	TSL:1	c.4173delA	p.Lys1391AsnfsTer15	frameshift	Exon 33 of 38	ENSP00000486629.1	O14647-2
	CHD2	ENST00000625662.3	TSL:5	n.*344delA		non_coding_transcript_exon	Exon 29 of 35	ENSP00000486007.2	A0A0D9SEU0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000774 AC: 14 AN: 180784 AF XY: 0.0000914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000818

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000574

Gnomad OTH exome AF: 0.000244

GnomAD4 exome AF: 0.0000137 AC: 19 AN: 1389718 Hom.: 0 Cov.: 30 AF XY: 0.0000174 AC XY: 12 AN XY: 690118

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

African (AFR) AF: 0.0000998 AC: 3 AN: 30062

American (AMR) AF: 0.000194 AC: 7 AN: 35996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24188

East Asian (EAS) AF: 0.00 AC: 0 AN: 37248

South Asian (SAS) AF: 0.0000261 AC: 2 AN: 76548

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 50990

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

European-Non Finnish (NFE) AF: 0.00000466 AC: 5 AN: 1072294

Other (OTH) AF: 0.0000176 AC: 1 AN: 56918

⚠️ 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Developmental and epileptic encephalopathy 94 (2)
1	-	-	Intellectual disability (1)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4

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: COSV67712028;