12-111327660-C-T

Variant names:

• chr12-111327660-C-T
• rs3847953
• NM_015267.4:c.2926+5080C>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.2926+5080C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 152,034 control chromosomes in the GnomAD database, including 20,019 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 0.46 (20019 hom., cov: 32)
• Consequence: CUX2 NM_015267.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0420
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUX2	NM_015267.4	c.2926+5080C>T		intron_variant	Intron 18 of 21	ENST00000261726.11	NP_056082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUX2	ENST00000261726.11	c.2926+5080C>T		intron_variant	Intron 18 of 21	1	NM_015267.4	ENSP00000261726.6

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69805 AN: 151916 Hom.: 19969 Cov.: 32

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.398

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.881

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.429

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

GnomAD4 genome AF: 0.460 AC: 69911 AN: 152034 Hom.: 20019 Cov.: 32 AF XY: 0.466 AC XY: 34639 AN XY: 74320

African (AFR) AF: 0.772 AC: 32010 AN: 41470

American (AMR) AF: 0.398 AC: 6076 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 751 AN: 3470

East Asian (EAS) AF: 0.880 AC: 4548 AN: 5166

South Asian (SAS) AF: 0.620 AC: 2986 AN: 4818

European-Finnish (FIN) AF: 0.325 AC: 3429 AN: 10560

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18862 AN: 67972

Other (OTH) AF: 0.429 AC: 906 AN: 2112

Alfa AF: 0.325 Hom.: 7968

Bravo AF: 0.479

Asia WGS AF: 0.686 AC: 2383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.8
DANN	Benign	0.71
PhyloP100		-0.042
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: rs3847953; hg19: chr12-111765464;