Genetic Variant NM_015267.4: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: 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

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.

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.*763T>C		3_prime_UTR	Exon 22 of 22	NP_056082.2	O14529
	CUX2	NM_001370598.1		c.*763T>C		3_prime_UTR	Exon 22 of 22	NP_001357527.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CUX2	ENST00000261726.11	TSL:1 MANE Select	c.*763T>C	3_prime_UTR	Exon 22 of 22	ENSP00000261726.6	O14529
CUX2	ENST00000933089.1		c.*763T>C	3_prime_UTR	Exon 21 of 21	ENSP00000603148.1
CUX2	ENST00000933090.1		c.*763T>C	3_prime_UTR	Exon 21 of 21	ENSP00000603149.1

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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over