NM_015267.4:c.238A>G

Variant names:

• chr12-111263776-A-G
• NM_015267.4:c.238A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015267.4(CUX2):​c.238A>G​(p.Lys80Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CUX2 NM_015267.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.35
• Publications: 0 publications found

Genes affected

CUX2 (HGNC:19347): (cut like homeobox 2) This gene encodes a protein which contains three CUT domains and a homeodomain; both domains are DNA-binding motifs. A similar gene, whose gene product possesses different DNA-binding activities, is located on chromosome on chromosome 7. Two pseudogenes of this gene have been identified on chromosomes 10 and 4. [provided by RefSeq, Jan 2013]

CUX2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 67

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015267.4. 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
	CUX2	NM_015267.4	MANE Select	c.238A>G	p.Lys80Glu	missense	Exon 4 of 22	NP_056082.2	O14529
	CUX2	NM_001370598.1		c.52A>G	p.Lys18Glu	missense	Exon 4 of 22	NP_001357527.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUX2	ENST00000261726.11	TSL:1 MANE Select	c.238A>G	p.Lys80Glu	missense	Exon 4 of 22	ENSP00000261726.6	O14529
	CUX2	ENST00000397643.3	TSL:1	c.418A>G	p.Lys140Glu	missense	Exon 5 of 8	ENSP00000380765.3	F5GWR6
	CUX2	ENST00000933089.1		c.190A>G	p.Lys64Glu	missense	Exon 3 of 21	ENSP00000603148.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.33
Sift	Benign	0.079	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.28		Loss of ubiquitination at K80 (P = 0.0087)
MVP		0.66
MPC		2.0
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.62
gMVP		0.43
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr12-111701580;