Genetic Variant CUX2:c.*763T>C (chr12-111349088-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015267.4(CUX2):c.*763T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 152,426 control chromosomes in the GnomAD database, including 18,227 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 0.43 ( 18218 hom., cov: 32)

Exomes 𝑓: 0.25 ( 9 hom. )

Consequence

CUX2
NM_015267.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.657

Publications

30 publications found

Variant links:

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

CUX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUX2	NM_015267.4 link	c.*763T>C		3_prime_UTR_variant	Exon 22 of 22	ENST00000261726.11	NP_056082.2	O14529

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUX2	ENST00000261726.11 link	c.*763T>C		3_prime_UTR_variant	Exon 22 of 22	1	NM_015267.4	ENSP00000261726.6		O14529

Frequencies

GnomAD3 genomes

AF:

0.425

AC:

64575

AN:

151926

Hom.:

18174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.734

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.451

Gnomad ASJ

AF:

0.145

Gnomad EAS

AF:

0.930

Gnomad SAS

AF:

0.581

Gnomad FIN

AF:

0.230

Gnomad MID

AF:

0.309

Gnomad NFE

AF:

0.231

Gnomad OTH

AF:

0.408

GnomAD4 exome

AF:

0.246

AC:

AN:

382

Hom.:

Cov.:

AF XY:

0.239

AC XY:

AN XY:

218

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.246

AC:

AN:

358

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.425

AC:

64686

AN:

152044

Hom.:

18218

Cov.:

AF XY:

0.431

AC XY:

32028

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.734

AC:

30452

AN:

41466

American (AMR)

AF:

0.452

AC:

6896

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

504

AN:

3466

East Asian (EAS)

AF:

0.929

AC:

4800

AN:

5166

South Asian (SAS)

AF:

0.580

AC:

2792

AN:

4814

European-Finnish (FIN)

AF:

0.230

AC:

2433

AN:

10572

Middle Eastern (MID)

AF:

0.318

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.231

AC:

15690

AN:

67982

Other (OTH)

AF:

0.407

AC:

861

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1461

2923

4384

5846

7307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

556

1112

1668

2224

2780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.303

Hom.:

11427

Bravo

AF:

0.457

Asia WGS

AF:

0.690

AC:

2397

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.4

(source)

DANN

Benign

0.21

PhyloP100

0.66

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over