rs886126

Variant names:

• chr12-111241410-C-T
• rs886126
• NM_015267.4:c.223-22351C>T

Variant summary

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

The NM_015267.4(CUX2):​c.223-22351C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 152,060 control chromosomes in the GnomAD database, including 11,244 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 0.34 (11244 hom., cov: 32)
• Consequence: CUX2 NM_015267.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 13 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=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUX2	NM_015267.4	c.223-22351C>T		intron_variant	Intron 3 of 21	ENST00000261726.11	NP_056082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUX2	ENST00000261726.11	c.223-22351C>T		intron_variant	Intron 3 of 21	1	NM_015267.4	ENSP00000261726.6
CUX2	ENST00000397643.3	c.403-22351C>T		intron_variant	Intron 4 of 7	1		ENSP00000380765.3
CUX2	ENST00000551604.2	n.59-22351C>T		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.342 AC: 52032 AN: 151942 Hom.: 11217 Cov.: 32

Gnomad AFR AF: 0.579

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.326

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

GnomAD4 genome AF: 0.343 AC: 52106 AN: 152060 Hom.: 11244 Cov.: 32 AF XY: 0.343 AC XY: 25499 AN XY: 74326

African (AFR) AF: 0.580 AC: 24016 AN: 41432

American (AMR) AF: 0.273 AC: 4161 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3470

East Asian (EAS) AF: 0.651 AC: 3362 AN: 5166

South Asian (SAS) AF: 0.468 AC: 2255 AN: 4818

European-Finnish (FIN) AF: 0.181 AC: 1918 AN: 10596

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.221 AC: 14998 AN: 67996

Other (OTH) AF: 0.327 AC: 690 AN: 2110

Alfa AF: 0.287 Hom.: 13132

Bravo AF: 0.360

Asia WGS AF: 0.487 AC: 1691 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.14
DANN	Benign	0.22
PhyloP100		-1.3
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: rs886126; hg19: chr12-111679214;