rs4766549

Variant names:

• chr12-111180528-T-G
• rs4766549
• NM_015267.4:c.64-33672T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015267.4(CUX2):​c.64-33672T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,220 control chromosomes in the GnomAD database, including 2,811 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2811 hom., cov: 33)
• Consequence: CUX2 NM_015267.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.361
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUX2	NM_015267.4	c.64-33672T>G		intron_variant	Intron 1 of 21	ENST00000261726.11	NP_056082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUX2	ENST00000261726.11	c.64-33672T>G		intron_variant	Intron 1 of 21	1	NM_015267.4	ENSP00000261726.6
CUX2	ENST00000397643.3	c.244-33672T>G		intron_variant	Intron 2 of 7	1		ENSP00000380765.3

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27157 AN: 152102 Hom.: 2810 Cov.: 33

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.0865

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.173

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.179 AC: 27184 AN: 152220 Hom.: 2811 Cov.: 33 AF XY: 0.186 AC XY: 13854 AN XY: 74426

African (AFR) AF: 0.209 AC: 8666 AN: 41530

American (AMR) AF: 0.163 AC: 2489 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0865 AC: 300 AN: 3470

East Asian (EAS) AF: 0.518 AC: 2673 AN: 5162

South Asian (SAS) AF: 0.292 AC: 1409 AN: 4826

European-Finnish (FIN) AF: 0.173 AC: 1834 AN: 10600

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9298 AN: 68012

Other (OTH) AF: 0.171 AC: 361 AN: 2114

Alfa AF: 0.149 Hom.: 5996

Bravo AF: 0.176

Asia WGS AF: 0.340 AC: 1180 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.6
DANN	Benign	0.60
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs4766549; hg19: chr12-111618332;