NM_001271.4:c.4231_4233delAAA

Variant names:

• chr15-93002269-CAAA-C
• rs746694647
• NM_001271.4:c.4231_4233delAAA

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_001271.4(CHD2):​c.4231_4233delAAA​(p.Lys1411del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000401 in 1,595,054 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (1 hom.)
• Consequence: CHD2 NM_001271.4 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001271.4
• BP6: Variant 15-93002269-CAAA-C is Benign according to our data. Variant chr15-93002269-CAAA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 60 Unknown,AD gene.

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.4231_4233delAAA	p.Lys1411del	conservative_inframe_deletion	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.4231_4233delAAA	p.Lys1411del	conservative_inframe_deletion	Exon 33 of 39	ENSP00000377747.4
	CHD2	ENST00000626874.2	TSL:1	c.4231_4233delAAA	p.Lys1411del	conservative_inframe_deletion	Exon 33 of 38	ENSP00000486629.1
	CHD2	ENST00000625662.3	TSL:5	n.*402_*404delAAA		non_coding_transcript_exon	Exon 29 of 35	ENSP00000486007.2

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151614 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000205 AC: 48 AN: 233952 AF XY: 0.000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00146

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: 0.0000416 AC: 60 AN: 1443440 Hom.: 1 AF XY: 0.0000334 AC XY: 24 AN XY: 718182

African (AFR) AF: 0.00 AC: 0 AN: 31976

American (AMR) AF: 0.00133 AC: 56 AN: 42104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 38466

South Asian (SAS) AF: 0.0000481 AC: 4 AN: 83246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103190

Other (OTH) AF: 0.00 AC: 0 AN: 59678

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151614 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 73982

African (AFR) AF: 0.0000242 AC: 1 AN: 41268

American (AMR) AF: 0.000197 AC: 3 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67910

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000106

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	CHD2-related disorder (1)
-	-	1	Developmental and epileptic encephalopathy 94 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=75/25	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs746694647; hg19: chr15-93545499;