rs1060503519

Variant names:

• chr15-92945835-A-G
• rs1060503519
• NM_001271.4:c.1168A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001271.4(CHD2):​c.1168A>G​(p.Lys390Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K390K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHD2 NM_001271.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.17
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-92945835-A-G is Pathogenic according to our data. Variant chr15-92945835-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 411854.

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.1168A>G	p.Lys390Glu	missense	Exon 11 of 39	NP_001262.3
	CHD2	NM_001042572.3		c.1168A>G	p.Lys390Glu	missense	Exon 11 of 13	NP_001036037.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD2	ENST00000394196.9	TSL:5 MANE Select	c.1168A>G	p.Lys390Glu	missense	Exon 11 of 39	ENSP00000377747.4
	CHD2	ENST00000626874.2	TSL:1	c.1168A>G	p.Lys390Glu	missense	Exon 11 of 38	ENSP00000486629.1
	CHD2	ENST00000420239.7	TSL:1	c.1168A>G	p.Lys390Glu	missense	Exon 11 of 13	ENSP00000406581.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1424192 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 707276

African (AFR) AF: 0.00 AC: 0 AN: 32036

American (AMR) AF: 0.00 AC: 0 AN: 39328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39210

South Asian (SAS) AF: 0.00 AC: 0 AN: 79634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091654

Other (OTH) AF: 0.00 AC: 0 AN: 58896

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Developmental and epileptic encephalopathy 94 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.43
Sift	Benign	0.14	T
Sift4G	Benign	0.074	T
Polyphen		0.85	P
Vest4		0.52
MutPred		0.50		Loss of ubiquitination at K390 (P = 0.0118)
MVP		0.90
MPC		0.69
ClinPred		0.71	D
GERP RS		5.3
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.19
gMVP		0.39

Splicing

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

Other links and lift over

dbSNP: rs1060503519; hg19: chr15-93489065;